Process for the preparation of chymase modulators

ABSTRACT

The present invention is a process for the preparation of chymase modulators, useful in the treatment of inflammatory and serine protease mediated disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/197,815, filed on Oct. 29, 2008, which is incorporated by referenceherein in its entirety.

FIELD OF THE INVENTION

The present invention is a process for the preparation of chymasemodulators, useful in the treatment of inflammatory and serine proteasemediated disorders.

SUMMARY OF THE INVENTION

The present invention is directed to a process for the preparation ofcompounds of formula (I)

-   -   wherein

is independently selected from the group consisting of aryl, heteroaryl,and benzo fused heterocyclyl; optionally substituted with R² and R³;

R² is one to three substituents independently selected from the groupconsisting of methoxy, C₂₋₆alkoxy, NH₂, NH(C₁₋₆alkyl), aryl, heteroaryl,halogen, hydroxy, and nitro;

wherein the C₁₋₄alkyl and C₂₋₆ alkoxy substituents of R² are optionallysubstituted with a substituent independently selected from the groupconsisting of —NR¹¹R¹², aryl, heteroaryl, one to three halogens andhydroxy; wherein R¹¹ and R¹² are substituents independently selectedfrom the group consisting of hydrogen, C₁₋₆ alkyl, and aryl; wherein theC₁₋₆alkyl substituent of R¹¹ or R¹² is optionally substituted with asubstituent selected from the group consisting of hydroxy, aryl,—C(═O)C₁₋₄alkoxy, and —NR¹⁵R¹⁶;

wherein said R¹⁵ and R¹⁶ are substituents independently selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, and aryl,

alternatively, R¹⁵ and R¹⁶ are taken together with the atoms to whichthey are attached to form a ring of five to seven members;

R³ is one to three substituents independently selected from the groupconsisting of C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkoxy, —OCH₂(C₂₋₆)alkenyl,NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆)dialkyl, —NHC(═O)Cy, —N(C₁₋₆alkyl)C(═O)Cy,—C(═O)C₁₋₄alkoxy, —C(═O)NR¹⁷R¹⁸, —C(═O)NHcycloalkyl,—C(═O)N(C₁₋₆alkyl)cycloalkyl, —C(═O)NHCy, —C(═O)N(C₁₋₆alkyl)Cy,—C(═O)Cy, —OC(═O)NR¹⁹R²⁰, halogen, hydroxy, nitro, cyano, aryl, andaryloxy;

wherein alkyl and alkoxy are optionally substituted with one to threesubstituents independently selected from the group consisting of—NR²¹R²², —NHcycloalkyl, —N(C₁₋₆alkyl)cycloalkyl, —NHCy,—N(C₁₋₆alkyl)Cy, aryl, heteroaryl, halogen, —C(═O)NR²³R²⁴,—OC(═O)NR²⁵R²⁶, —C(═O)(C₁₋₄)alkoxy, and —C(═O)Cy; wherein alkenyl isoptionally substituted on a terminal carbon with aryl and —C(═O)NR²⁷R²⁸;and, wherein aryl and cycloalkyl are optionally substituted with one tothree substituents independently selected from R¹⁴;

each R¹⁴ is independently hydrogen, C₁₋₆alkyl, C₁₋₆alkoxy, C₂₋₆alkenyl,C₁₋₆alkylthio, —NH₂, —NH(C₁₋₆)alkyl, —N(C₁₋₆)dialkyl, aryl, heteroaryl,aryloxy, heteroaryloxy, halogen, hydroxy, or nitro; wherein any one ofthe foregoing C₁₋₆alkyl- or C₁₋₆alkoxy-containing substituents of R¹⁴ isoptionally substituted on a terminal carbon atom with a substituentselected from —NR²⁹R³⁰, aryl, heteroaryl, one to three halogen atoms, orhydroxy;

R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵ and R²⁶ are substituentsindependently selected from the group consisting of hydrogen, C₁₋₆alkyland aryl; wherein the C₁₋₆alkyl and aryl are each optionally substitutedwith hydroxy, aryl, aryloxy, —C(═O)-aryl, —C(═O)C₁₋₄alkoxy, NH₂,—NH(C₁₋₆alkyl), or —N(C₁₋₆)dialkyl; alternatively, R¹⁷ and R¹⁸, R¹⁹ andR²⁰, R²¹ and R²², R²³ and R²⁴ or R²⁵ and R²⁶ are taken together with theatoms to which they are attached to form a ring of five to sevenmembers;

R²⁷ and R²⁸ are independently hydrogen; C₁₋₆alkyl optionally substitutedwith hydroxy, aryl, —C(═O)C₁₋₄alkoxy, NH₂, —NH(C₁₋₆alkyl) or—N(C₁₋₆)dialkyl; or aryl; alternatively, R²⁷ and R²⁸ are taken togetherwith the atoms to which they are attached to form a ring of five toseven members;

R²⁹ and R³⁰ are independently hydrogen, C₁₋₆alkyl optionally substitutedwith hydroxy, aryl, —C(═O)C₁₋₄alkoxy, NH₂, —NH(C₁₋₆alkyl), or—N(C₁₋₆)dialkyl; or aryl; alternatively, R²⁹ and R³⁰ are taken togetherwith the atoms to which they are attached to form a ring of five toseven members;

Cy is a heterocyclyl optionally substituted with a substituent selectedfrom the group consisting of C₁₋₆ alkyl, C₁₋₆alkylC(═O)C₁₋₆alkyl,—C₁₋₆alkylC(═O)C₁₋₆alkoxy, C₁₋₆alkylC(═O)aryl, —C(═O)(C₁₋₆)alkyl,—C(═O)(C₁₋₆)alkoxy, —C(═O)aryl, —SO₂aryl, aryl, heteroaryl, andheterocyclyl; wherein aryl and the aryl portion of theC₁₋₆alkylC(═O)aryl, —C(═O)aryl and —SO₂aryl are optionally substitutedwith one to three substituents independently selected from the groupconsisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen, hydroxy, NH₂,NH(C₁₋₆alkyl), or —N(C₁₋₆)dialkyl; and wherein heterocyclyl isoptionally substituted with aryl, one to three halogen atoms, or one tothree oxo substituents; and, wherein heterocyclyl is optionallyspiro-fused to said Cy;

R⁵ is selected from the group consisting of hydrogen;

C₁₋₃alkyl optionally substituted with NH₂, —NH(C₁₋₆)alkyl,C₁₋₆alkylcarbonyloxy, C₁₋₆alkoxycarbonyloxy, C₁₋₆alkylcarbonylthio,(C₁₋₆)alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl, one to threehalogens, or hydroxy;

and aryl optionally substituted with C₁₋₆alkyl, C₁₋₆alkoxy, C₂₋₆alkenyl, —NH₂, —NH(C₁₋₆)alkyl, —N(C₁₋₆)dialkyl, aryl, heteroaryl,aryloxy, heteroaryloxy, halogen, hydroxy, or nitro;

alternatively, when R⁶ is C₁₋₈alkoxy, R⁵ and R⁶ are taken together withthe atoms to which they are attached to form a 5-8 membered monocyclicring;

and provided that R⁵ is other than C₁₋₃alkyl substituted withdi(C₁₋₆)alkylamino-carbonyl when ring system A is 3,4-difluoro-phenyl,R⁶ is OH, and Z-R⁴ is 5-chloro-benzothiophen-3-yl; and provided that R⁵is other than C₁₋₃alkyl substituted with C₁₋₆alkylcarbonylthio when ringsystem A is 3,4-difluoro-phenyl, R⁶ is CH₃, and Z-R⁴ is5-chloro-benzothiophen-3-yl;

R⁶ is selected from the group consisting of C₁₋₆alkyl, C₁₋₈alkoxy,heteroaryl, aryl, and hydroxy; wherein alkyl and C₁₋₈alkoxy areoptionally substituted on a terminal carbon atom with a substituentselected from C₁₋₃alkoxy, aryl, or hydroxy; and alkoxy is optionallysubstituted on a terminal carbon with a substituent independentlyselected from the group consisting of C₁₋₆alkylcarbonyloxy, anddi(C₁₋₆)alkylaminocarbonyl; and wherein heteroaryl and aryl areoptionally substituted with one to three substituents independentlyselected from the group consisting of aryl, hydroxy, C₁₋₆alkoxy, andhalogen;

Z is a bicyclic aryl or bicyclic heteroaryl;

R⁴ is one to three substituents selected from the group consisting of H,C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkoxy, aryl(C₂₋₆)alkenyl, halogen,—C(═O)Cy, —C(═O)NR³¹R³², aryl, —CO₂H, oxo, and cyano; wherein the alkyland alkoxy are optionally substituted with a substituent independentlyselected from the group consisting of —NR³³R³⁴, aryl, one to threehalogen atoms, and hydroxy; wherein the aryl is optionally substitutedwith a substituent independently selected from the group consisting ofhydrogen, C₁₋₆alkyl, C₁₋₆alkoxy, aryl, halogen, hydroxy, and nitro;

wherein said R³¹, R³², R³³, and R³⁴ are substituents independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, and aryl,wherein alkyl is optionally substituted with hydroxy, aryl,—C(═O)C₁₋₄alkoxy, NH₂, NH(C₁₋₆alkyl), or —N(C₁₋₆)dialkyl; or R³¹ withR³², or R³³ with R³⁴ are optionally taken together with the atoms towhich they are attached to form a ring of five to seven members;

and pharmaceutically acceptable salts thereof; comprising the steps of

(a) reacting a compound of formula (IV), wherein PG¹ is an oxygenprotecting group; with a source of nitrogen; in the presence of CO₂ gas;in an organic solvent; to yield the corresponding compound of formula(IX);

(b) reacting the compound of formula (IX) with a compound of formula(XVI); in the presence of CuI; in the presence of an inorganic base; inthe presence of a ligand; in an organic solvent or mixture thereof; toyield the corresponding compound of formula (XVII);

(c) de-protecting the compound of formula (XVII); to yield thecorresponding compound of formula (Ia); and

(d) optionally reacting the compound of formula (Ia) with a compound offormula (XVIII), wherein Q¹ is a leaving group and wherein R⁵ is otherthan hydrogen; in the presence of an organic base; in an organicsolvent; to yield the corresponding compound of formula (Ib), wherein R⁵is other than hydrogen.

The present invention is further directed to processes for thepreparation of compound of formula (I)

wherein

R², R³, Z, R⁴, R⁵ and R⁶ are as described herein above; andpharmaceutically acceptable salt thereof; comprising the steps of

(a) reacting a compound of formula (IV) with CO₂; in the presence of abase; in an organic solvent or mixture thereof; to yield thecorresponding compound of formula (V);

(b) activating the compound of formula (V); to yield the correspondingcompound of formula (A1); wherein Y¹ is selected from the groupconsisting of chloro, —O—C(O)—C₁₋₄alkyl and 1-imidazolyl;

(c) reacting the compound of formula (A1) with a source of ammonia; inan organic solvent; to yield the corresponding compound of formula (IX);

(d) reacting the compound of formula (IX) with a compound of formula(XVI); in the presence of CuI; in the presence of an inorganic base; inthe presence of a ligand; in an organic solvent or mixture thereof; toyield the corresponding compound of formula (XVII);

(e) de-protecting the compound of formula (XVII); to yield thecorresponding compound of formula (Ia); and

(f) optionally reacting the compound of formula (Ia) with a compound offormula (XVIII), wherein Q¹ is a leaving group and wherein R⁵ is otherthan hydrogen; in the presence of an organic base; in an organicsolvent; to yield the corresponding compound of formula (Ib), wherein R⁵is other than hydrogen.

Step (b) of said process is preferably accomplished by:

reacting the compound of formula (V) with a source of chlorine; in anorganic solvent; to yield the corresponding compound of formula (A1)wherein Y¹ is Cl; or

reacting the compound of formula (V) with a C₁₋₄alkyl chloroformate; inan organic solvent; to yield the corresponding compound of formula (A1),

wherein Y is —O—C(O)—C₁₋₄alkyl; or

reacting the compound of formula (V) with CDI; in an organic solvent; toyield the corresponding compound of formula (A1), wherein Y¹ is1-imidazolyl.

The present invention is further directed to processes for thepreparation of compounds of formula (I)

wherein

R², R³, Z, R⁴, R⁵ are as described herein above and R⁶ is hydroxy; andpharmaceutically acceptable salts thereof; comprising the steps of

(a) reacting a compound of formula (X), wherein PG¹ is an oxygenprotecting group and PG² is an oxygen protecting group; with a source ofnitrogen; in the presence of CO₂ gas; in an organic solvent; to yieldthe corresponding compound of formula (XV);

(b) reacting the compound of formula (XV) with a compound of formula(XVI); in the presence of CuI; in the presence of an inorganic base; inthe presence of a ligand; in an organic solvent or mixture thereof; toyield the corresponding compound of formula (XIX);

(c) de-protecting the compound of formula (XIX); to yield thecorresponding compound of formula (Ic); and

(d) optionally reacting the compound of formula (Ic) with a compound offormula (XVIII), wherein Q¹ is a leaving group and wherein R⁵ is otherthan hydrogen; in the presence of an organic base; in an organicsolvent; to yield the corresponding compound of formula (Id), wherein R⁵is other than hydrogen.

The present invention is further directed to a process for thepreparation of compounds of formula (I)

wherein

R², R³, Z, R⁴, R⁵ are as described herein above and R⁶ is hydroxy; andpharmaceutically acceptable salts thereof; comprising the steps of

(a) reacting a compound of formula (X) with CO₂; in the presence of abase; in an organic solvent or mixture thereof; to yield thecorresponding compound of formula (XI);

(b) activating the compound of formula (XI); to yield the correspondingcompound of formula (A2), wherein Y¹ is selected from the groupconsisting of chloro, —O—C(O)—C₁₋₄alkyl and 1-imidazolyl;

(c) reacting the compound of formula (A2) with a source of ammonia; inan organic solvent; to yield the corresponding compound of formula (XV);

(d) reacting the compound of formula (XV) with a compound of formula(XVI); in the presence of CuI; in the presence of an inorganic base; inthe presence of a ligand; in an organic solvent or mixture thereof; toyield the corresponding compound of formula (XIX);

(e) de-protecting the compound of formula (XIX); to yield thecorresponding compound of formula (Ic); and

(f) optionally reacting the compound of formula (Ic) with a compound offormula (XVIII), wherein Q¹ is a leaving group and wherein R⁵ is otherthan hydrogen; in the presence of an organic base; in an organicsolvent; to yield the corresponding compound of formula (Id), wherein R⁵is other than hydrogen.

Step (b) of said process is preferably accomplished by:

reacting the compound of formula (V) with a source of chlorine; in anorganic solvent; to yield the corresponding compound of formula (A1)wherein Y¹ is Cl; or

reacting the compound of formula (V) with a C₁₋₄alkyl chloroformate; inan organic solvent; to yield the corresponding compound of formula (A1),wherein Y is —O—C(O)—C₁₋₄alkyl; or

-   -   reacting the compound of formula (V) with CDI; in an organic        solvent; to yield the corresponding compound of formula (A1),        wherein Y¹ is 1-imidazolyl.

The present invention is further directed to compounds of formula (L)

wherein

PG¹ is an oxygen protecting group;

R¹⁰ is selected from the group consisting of —O-PG² and R⁶;

PG² is an oxygen protecting group

R⁶ is selected from the group consisting of C₁₋₆alkyl, C₁₋₈alkoxy,heteroaryl, aryl, and hydroxy; wherein alkyl and C₁₋₈alkoxy areoptionally substituted on a terminal carbon atom with a substituentselected from C₁₋₃alkoxy, aryl, or hydroxy; and alkoxy is optionallysubstituted on a terminal carbon with a substituent independentlyselected from the group consisting of C₁₋₆alkylcarbonyloxy, anddi(C₁₋₆)alkylaminocarbonyl; and wherein heteroaryl and aryl areoptionally substituted with one to three substituents independentlyselected from the group consisting of aryl, hydroxy, C₁₋₆alkoxy, andhalogen.

Z is a bicyclic aryl or bicyclic heteroaryl;

R⁴ is one to three substituents selected from the group consisting of H,C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkoxy, aryl(C₂₋₆)alkenyl, halogen,—C(═O)Cy, —C(═O)NR³¹R³², aryl, —CO₂H, oxo, and cyano; wherein the alkyland alkoxy are optionally substituted with a substituent independentlyselected from the group consisting of —NR³³R³⁴, aryl, one to threehalogen atoms, and hydroxy; wherein the aryl is optionally substitutedwith a substituent independently selected from the group consisting ofhydrogen, C₁₋₆alkyl, C₁₋₆alkoxy, aryl, halogen, hydroxy, and nitro;

wherein said R³¹, R³², R³³, and R³⁴ are substituents independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, and aryl,wherein alkyl is optionally substituted with hydroxy, aryl,—C(═O)C₁₋₄alkoxy, NH₂, NH(C₁₋₆alkyl), or —N(C₁₋₆)dialkyl; or R³¹ withR³², or R³³ with R³⁴ are optionally taken together with the atoms towhich they are attached to form a ring of five to seven members;

or a pharmaceutically acceptable salt thereof.

The present invention is further directed to a process for thepreparation of compounds of formula (IX)

wherein PG¹, R⁶, Z and R⁴ substituents as described herein above(compounds of formula (L) wherein R¹⁰ is R⁶); and pharmaceuticallyacceptable salts thereof; comprising the step of

(a) reacting a compound of formula (IV), wherein PG¹ is an oxygenprotecting group; with a source of nitrogen; in the presence of CO₂ gas;in an organic solvent; to yield the corresponding compound of formula(IX).

The present invention is further directed to processes for thepreparation of compounds of formula (IX)

wherein PG¹, R⁶, Z and R⁴ are as described herein above (compounds offormula (L) wherein R¹⁰ is R⁶); and pharmaceutically acceptable saltsthereof; comprising the step of

(a) reacting a compound of formula (IV) with CO₂; in the presence of abase; in an organic solvent or mixture thereof; to yield thecorresponding compound of formula (V);

(b) activating the compound of formula (V); to yield the correspondingcompound of formula (A1); wherein Y¹ is selected from the groupconsisting of chloro, —O—C(O)—C₁₋₄alkyl and 1-imidazolyl;

(c) reacting the compound of formula (A1) with a source of ammonia; inan organic solvent; to yield the corresponding compound of formula (IX).

Step (b) of said process is preferably accomplished by:

reacting the compound of formula (V) with a source of chlorine; in anorganic solvent; to yield the corresponding compound of formula (A1)wherein Y¹ is Cl; or

reacting the compound of formula (V) with a C₁₋₄alkyl chloroformate; inan organic solvent; to yield the corresponding compound of formula (A1),wherein Y is —O—C(O)—C₁₋₄alkyl; or

reacting the compound of formula (V) with CDI; in an organic solvent; toyield the corresponding compound of formula (A1), wherein Y¹ is1-imidazolyl.

The present invention is further directed to processes for thepreparation of compounds of formula (XV)

wherein PG¹, PG², Z and R⁴ are as described herein above (compounds offormula (L) wherein R¹⁰ is —O-PG²); and pharmaceutically acceptablesalts thereof; comprising the step of

(a) reacting a compound of formula (X), wherein PG¹ is an oxygenprotecting group and PG² is an oxygen protecting group; with a source ofnitrogen; in the presence of CO₂ gas; in an organic solvent; to yieldthe corresponding compound of formula (XV).

The present invention is further directed to processes for thepreparation of compounds of formula (XV)

wherein PG¹, PG², Z and R⁴ are as described herein above (compounds offormula (L) wherein R¹⁰ is —O-PG²); and pharmaceutically acceptablesalts thereof; comprising the step of

-   -   (a) reacting a compound of formula (X) with CO₂; in the presence        of a base; in an organic solvent or mixture thereof; to yield        the corresponding compound of formula (XI);

(b) activating the compound of formula (XI); to yield the correspondingcompound of formula (A2), wherein Y¹ is selected from the groupconsisting of chloro, —O—C(O)—C₁₋₄alkyl and 1-imidazolyl;

(c) reacting the compound of formula (A2) with a source of ammonia; inan organic solvent; to yield the corresponding compound of formula (XV).

Step (b) of said process is preferably accomplished by:

reacting the compound of formula (V) with a source of chlorine; in anorganic solvent; to yield the corresponding compound of formula (A1)wherein Y¹ is Cl; or

reacting the compound of formula (V) with a C₁₋₄alkyl chloroformate; inan organic solvent; to yield the corresponding compound of formula (A1),wherein Y is —O—C(O)—C₁₋₄alkyl; or

reacting the compound of formula (V) with CDI; in an organic solvent; toyield the corresponding compound of formula (A1), wherein Y¹ is1-imidazolyl.

The present invention is further directed to a process for thepreparation of a compound of formula (III)

comprising the step of

(a) reacting a compound of formula (II) with a brominating agent; in thepresence of a catalyst; in a mixture of water and an organic solvent; toyield the corresponding compound of formula (III).

The present invention is further directed to a product preparedaccording to any of the processes described herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a process for the preparation ofcompound of formula (I)

wherein Z, R⁴, R⁵, R⁶, R², R³ and

are as herein defined; and pharmaceutically acceptable salts thereof.The compounds of formula (I), prepared according to the processesdescribed herein, are useful in methods for treating or ameliorating aserine protease-mediated disorder, as disclosed in U.S. Pat. No.7,459,444, issued Dec. 2, 2008, which is incorporated by referenceherein in its entirety.

In particular, the compounds of formula (I) are useful in treating orameliorating a chymase mediated disorder such as, but not limited to,allergic rhinitis, viral rhinitis, asthma, chronic obstructive pulmonarydiseases, bronchitis, pulmonary emphysema, acute lung injury (e.g. adult(acute) respiratory distress syndrome), psoriasis, arthritis,reperfusion injury, ischemia, hypertension, hypercardia, myocardialinfarction, heart failure damage associated with myocardial infarction,cardiac hypertrophy, arteriosclerosis, saroidosis, vascular stenosis orrestenosis (e.g., associated with vascular injury, angioplasty, vascularstents or vascular grafts), pulmonary fibrosis, kidney fibrosis (e.g.,associated with glomerulonephritis), liver fibrosis, post surgicaladhesion formation, systemic sclerosis, keloid scars, rheumatoidarthritis, bullous pemphigiod, and atherosclerosis. Additionally, thecompounds of formula (I) are useful for modulating wound healing andremodeling (e.g., cardiac hypertrophy) as well as immune modulation.

In an embodiment, the present invention is directed to a process for thepreparation of compounds of formula (I-S)

wherein

R² and R³ are each independently selected from halogen;

R⁵ is selected from the group consisting of hydrogen and C₁₋₃alkyl;

wherein the C₁₋₃alkyl is optionally substituted withC₁₋₆alkylcarbonyloxy or C₁₋₆alkoxycarbonyloxy;

R⁶ is hydroxy;

and pharmaceutically acceptable salts thereof; as described in moredetail herein.

In an embodiment, the present invention is directed to processes for thepreparation of compounds of formula (I) wherein R⁶ is other thanhydroxy.

In another embodiment, the present invention is directed to processesfor the preparation of compounds of formula (I) wherein R⁶ is C₁₋₄alkyl.

In another embodiment, the present invention is directed to processesfor the preparation of compounds of formula (I) wherein R⁶ is hydroxy.

In an embodiment, the present invention is directed to processes for thepreparation of compounds of formula (I) wherein R⁵ is hydrogen.

In another embodiment, the present invention is directed to processesfor the preparation of compounds of formula (I) wherein R⁵ is selectedfrom the group consisting of —CH₂—O—C(O)-t-butyl and—CH₂—O—C(O)—O-isopropyl.

In another embodiment, the present invention is directed to a processfor the preparation of a compound of formula (I-A)

also known asE-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinicacid, and pharmaceutically acceptable salts thereof.

In another embodiment, the present invention is directed to a processfor the preparation of a compound of formula (I-B)

also known asE-{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]methyl}-phosphonicacid, and pharmaceutically acceptable salts thereof.

In another embodiment, the present invention is directed to a processfor the preparation of a compound of formula (I-C)

also known asE-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]methyl}-hydroxy-phosphinoyloxymethylester 2,2-dimethyl-propionic acid, and pharmaceutically acceptable saltsthereof.

In another embodiment, the present invention is directed to a processfor the preparation of a compound of formula (I-D)

also known asE-{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-methyl}-phosphonicacid monoisopropoxycarbonyloxymethyl ester, and pharmaceuticallyacceptable salts thereof; as described in more detail herein.

In another embodiment, the present invention is directed to a processfor the preparation of a compound of formula (I-E)

also known asE-{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dichloro-phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinicacid, and pharmaceutically acceptable salts thereof.

In another embodiment, the present invention is directed to a processfor the preparation of a compound of formula (I-F)

also known asE-{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dichloro-phenyl)-vinylcarbamoyl]-methyl}-phosphonicacid, and pharmaceutically acceptable salts thereof.

In another embodiment, the present invention is directed to a processfor the preparation of a compound of formula (I-G)

also known asE-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dichloro-phenyl)-vinylcarbamoyl]-methyl}-hydroxy-phosphinoyloxymethylester 2,2-dimethyl-propionic acid, and pharmaceutically acceptable saltsthereof.

In another embodiment, the present invention is directed to a processfor the preparation of a compound of formula (I-H)

also known asE-{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dichloro-phenyl)-vinylcarbamoyl]-methyl}-phosphonicacid monoisopropoxycarbonyloxymethyl ester, and pharmaceuticallyacceptable salts thereof; as described in more detail hereinafter.

The present invention is further directed to compounds of formula (L)

wherein PG¹, R¹⁰, Z and R⁴ are as described herein above; andpharmaceutically acceptable salts thereof.

In an embodiment, the present invention is further directed to compoundsof formula (L) wherein R¹⁰ is R⁶; herein referred to as compounds offormula (IX)

In an embodiment, the present invention is further directed to compoundsof formula (L) wherein R¹⁰ is O-PG²; herein referred to as compounds offormula (XV)

The present invention is further directed to processes for thepreparation of compounds of formula (L), as described in more detailherein.

In an embodiment, the present invention is directed to processes for thepreparation of the compounds of formula (IX), as described in moredetail herein. The compounds of formula (IX) are useful as intermediatesin the synthesis of the compounds of formula (I).

In another embodiment, the present invention is directed processes forthe preparation of compounds of formula (XV), as described in moredetail herein. The compounds of formula (XV) are useful as intermediatesin the synthesis of the compounds of formula (I), more particularlycompounds of formula (I) wherein R⁶ is hydroxy.

In another embodiment, the present invention is directed to processesfor the preparation of a compound of formula (IX-S)

wherein PG¹ is an oxygen protecting group (preferably PG¹ is selectedfrom the group consisting of C₁₋₄alkyl);

R⁶ is selected from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy,heteroaryl, aryl, and hydroxy; wherein alkyl and C₁₋₈alkoxy areoptionally substituted on a terminal carbon atom with a substituentselected from C₁₋₃alkoxy, aryl, or hydroxy; and alkoxy is optionallysubstituted on a terminal carbon with a substituent independentlyselected from the group consisting of C₁₋₆alkylcarbonyloxy, anddi(C₁₋₆)alkylaminocarbonyl; and wherein heteroaryl and aryl areoptionally substituted with one to three substituents independentlyselected from the group consisting of aryl, hydroxy, C₁₋₆alkoxy, andhalogen; as described in more detail herein.

In another embodiment, the present invention is directed to a processfor the preparation of a compound of formula (IX-S) wherein R⁶ ismethyl.

In another embodiment, the present invention is directed to a processfor the preparation of a compound of formula (IX-S) wherein R⁶ ishydroxy.

In another embodiment, the present invention is directed to a processfor the preparation of a compound of formula (IX-S) wherein PG¹ isethyl; and

wherein R⁶ is selected from the group consisting of methyl and hydroxy.

In another embodiment, the present invention is directed to processesfor the preparation of a compound of formula (XV-S)

wherein PG¹ is an oxygen protecting group and PG² is an oxygenprotecting group; as described in more detail herein.

In an embodiment of the present invention, PG¹ and PG² are the sameoxygen protecting group.

In another embodiment of the present invention, PG¹ and PG² aredifferent oxygen protecting groups.

In another embodiment of the present invention, PG¹ and PG² are eachindependently selected from C₁₋₄alkyl.

In another embodiment of the present invention, PG¹ and PG² are the sameand are selected from the group consisting of methyl and ethyl.

The present invention is directed to a process for the preparation of acompound selected from the group consisting of a compound of formula(III)

as described in more detail herein.

In an embodiment of the present invention, the compound of formula (III)is present in an excess of its trans isomer of greater than or equal toabout 90%, preferably greater than or equal to about 95%, morepreferably greater than or equal to about 98%, more preferably greaterthan or equal to about 99%.

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (I) wherein

is selected from group consisting of naphthyl, benzothiazolyl,benzothiophenyl, quinolinyl, isoquinolinyl, dihydronaphthyl, indanyl,tetralinyl and benzodioxolyl when n is equal to zero; and A is selectedfrom phenyl, pyridin-2-yl, or pyridin-3-yl when n is equal to one.

In another embodiment, the present invention is directed to a processfor the preparation of a compound of formula (I) wherein

is selected from phenyl, pyridin-2-yl, or pyridin-3-yl when n is equalto one.

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (I) wherein R² is a substituentindependently selected from the group consisting of C₁₋₄alkyl, methoxy,C₂₋₄alkoxy, hydroxy, halogen, and —NH₂.

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (I) wherein R³ is one to threesubstituents independently selected from the group consisting ofC₁₋₆alkyl, C₁₋₆alkoxy, —NR¹⁹R²⁰, —NHC(═O)Cy, —C(═O)NR¹⁷R¹⁸,—C(═O)NHcycloalkyl, —C(═O)N(C₁₋₆alkyl)cycloalkyl, halogen, and aryl;wherein alkyl and alkoxy are optionally substituted on a terminal carbonatom with one to three fluorine atoms, —NH₂, —NHCy, or —N(C₁₋₄alkyl)Cy;and wherein aryl and cycloalkyl are optionally substituted with a groupindependently selected from R¹⁴.

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (I) wherein R⁵ is hydrogen orC₁₋₃alkyl optionally substituted with C₁₋₆alkylcarbonyloxy,C₁₋₆alkoxycarbonyloxy, C₁₋₆alkylcarbonylthio, (C₁₋₆)alkylaminocarbonyl,or di(C₁₋₆)alkylaminocarbonyl; and alternatively, when R⁶ is C₁₋₈alkoxy,R⁵ and R⁶ are taken together with the atoms to which they are attachedto form a 6-membered monocyclic ring; and provided that R⁵ is other thanC₁₋₃alkyl substituted with di(C₁₋₆)alkylamino-carbonyl when ring systemA is 3,4-difluoro-phenyl, R⁶ is OH, and Z-R⁴ is5-chloro-benzothiophen-3-yl; and provided that R⁵ is other thanC₁₋₃alkyl substituted with C₁₋₆alkylcarbonylthio when ring system A is3,4-difluoro-phenyl, R⁶ is CH₃, and Z-R⁴ is 5-chloro-benzothiophen-3-yl.

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (I) wherein R⁶ is selected from thegroup consisting of methyl, ethyl, methoxypropyl, phenethyl,benzo[1,3]dioxol-5-yl-propyl, hydroxy, and C₁₋₃alkoxy optionallysubstituted with C₁₋₆alkylcarbonyloxy, and di(C₁₋₆)alkylamino-carbonyl.

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (I) wherein Z is independentlyselected from the group consisting of indolyl, benzothiophenyl,naphthalenyl, quinolinyl, isoquinolinyl and benzothiazolonyl.

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (I) wherein R⁴ is one to threesubstituents selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkenyl, aryl(C₂₋₆)alkenyl, halogen, and —C(═O)Cy; wherein aryl isoptionally substituted with a substituent selected from halogen orC₁₋₄alkoxy.

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (I) wherein

is a ring system of the formula:

wherein the a¹ portion of said a¹a² is optionally substituted with R²;and the a² portion is optionally substituted with R³ and n is 0. Inanother embodiment, the present invention is directed to a process forthe preparation of a compound of formula (I) wherein

is a ring system of the formula:

and wherein the a² portion is aromatic and

is selected from group consisting of naphthyl, benzothiazolyl,benzothiophenyl, quinolinyl, isoquinolinyl, dihydronaphthyl, indanyl,tetralinyl and benzodioxolyl.

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (I) wherein R² is a substituentindependently selected from the group consisting of C₁₋₄alkyl, methoxy,C₂₋₄alkoxy, hydroxy, halogen, and —NH₂.

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (I) wherein R³ is one to threesubstituents independently selected from the group consisting ofC₁₋₆alkyl, C₁₋₆alkoxy, —NR¹⁹R²⁰, —NHC(═O)Cy, —C(═O)NR¹⁷R¹⁸,—C(═O)NHcycloalkyl, —C(═O)N(C₁₋₆alkyl)cycloalkyl, halogen, and aryl;wherein alkyl and alkoxy are optionally substituted on a terminal carbonatom with one to three fluorine atoms, —NH₂, NHCy, or —N(C₁₋₄alkyl)Cy;and wherein aryl and cycloalkyl are optionally substituted with a groupindependently selected from R¹⁴.

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (I) wherein R⁵ is hydrogen orC₁₋₃alkyl optionally substituted with C₁₋₆alkylcarbonyloxy,C₁₋₆alkoxycarbonyloxy, C₁₋₆alkylcarbonylthio, (C₁₋₆)alkylaminocarbonyl,or di(C₁₋₆)alkylaminocarbonyl; and alternatively, when R⁶ is C₁₋₈alkoxy,R⁵ and R⁶ are taken together with the atoms to which they are attachedto form a 6-membered monocyclic ring; provided that R⁵ is other thanC₁₋₃alkyl substituted with di(C₁₋₆)alkylaminocarbonyl when ring system Ais 3,4-difluoro-phenyl, R⁶ is OH, and Z-R⁴ is5-chloro-benzothiophen-3-yl; and provided that R⁵ is other thanC₁₋₃alkyl substituted with C₁₋₆alkylcarbonylthio when ring system A is3,4-difluoro-phenyl, R⁶ is CH₃, and Z-R⁴ is 5-chloro-benzothiophen-3-yl.

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (I) wherein R⁶ is selected from thegroup consisting of methyl, ethyl, methoxypropyl, phenethyl,benzo[1,3]dioxol-5-yl-propyl, hydroxy, and C₁₋₃alkoxy optionallysubstituted with C₁₋₆alkylcarbonyloxy, and di(C₁₋₆)alkylamino-carbonyl.

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (I) wherein Z is independentlyselected from the group consisting of indolyl, benzothiophenyl,naphthalenyl, quinolinyl, isoquinolinyl, and benzothiazolone.

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (I) wherein R⁴ is one to threesubstituents selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkenyl, aryl(C₂₋₆)alkenyl, halogen, and —C(═O)Cy; wherein aryl isoptionally substituted with a substituent selected from halogen orC₁₋₄alkoxy.

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (I) wherein R¹, ring A, R², R³, R⁵,R⁶, Z, and R⁴ are selected from the group consisting of

R⁵ R⁶ Z-R⁴ 3,4-difluoro-phenyl H OH 5-Cl- benzothiophen-3-yl4-fluoro-phenyl H OH 5-Cl-N-methyl-indol-3-yl 3-fluoro-phenyl H CH₃5-Cl-N-methyl-indol-3-yl 3,4-difluoro-phenyl H CH₃5-Cl-N-methyl-indol-3-yl 4-amino-phenyl H OH 5-Cl-benzothiophen-3-ylPhenyl H CH₃ 5-Cl-benzothiophen-3-yl 3-fluoro-phenyl H CH₃5-Cl-benzothiophen-3-yl 3,4,5-trifluoro- H CH₃ 5-Cl-benzothiophen-3-ylphenyl 3,4-difluoro-phenyl H CH₃ 5-Cl-benzothiophen-3-yl phenyl H OH5-Cl-benzothiophen-2-yl 4-fluoro-phenyl H OH 5-Cl-benzothiophen-3-yl2-fluoro-phenyl H CH₃ 5-Cl-benzothiophen-3-yl 4-fluoro-phenyl H CH₃5-Cl-benzothiophen-3-yl pyridin-3-yl H OH 5-Cl-benzothiophen-3-yl3,4-difluoro-phenyl H CH₂CH₃ 5-Cl-benzothiophen-3-yl phenyl H OHnaphthalen-1-yl 4-methoxy-phenyl H OH 5-Cl-benzothiophen-3-yl4-methyl-phenyl H OH 5-Cl-benzothiophen-2-yl 3,4-dimethoxy- H OH5-Cl-benzothiophen-3-yl phenyl 4-hydroxy-phenyl H OH5-Cl-benzothiophen-3-yl 4-chloro-phenyl H CH₃ 5-Cl-benzothiophen-3-yl4-trifluoromethyl- H OH 5-Cl-benzothiophen-3-yl phenyl 2-methoxy-phenylH CH₃ 5-Cl-benzothiophen-3-yl 2-nitro-phenyl H CH₃5-Cl-benzothiophen-3-yl 2- H CH₃ 5-Cl-benzothiophen-3-ylmethylcarbonyloxy- phenyl 2-hydroxy-phenyl H CH₃ 5-Cl-benzothiophen-3-ylpyridin-2-yl H CH₃ 5-Cl-benzothiophen-3-yl 2-amino-phenyl H CH₃5-Cl-benzothiophen-3-yl 3-trifluoromethyl- H CH₃ 5-Cl-benzothiophen-3-ylphenyl 3-trifluoromethoxy- H CH₃ 5-Cl-benzothiophen-3-yl phenyl3-methoxy-phenyl H CH₃ 5-Cl-benzothiophen-3-yl 2-methyl-phenyl H CH₃5-Cl-benzothiophen-3-yl 2,6-difluoro-phenyl H CH₃5-Cl-benzothiophen-3-yl 4-cyano-phenyl H CH₃ 5-Cl-benzothiophen-3-yl2-ureido-phenyl H CH₃ 5-Cl-benzothiophen-3-yl 2- H CH₃5-Cl-benzothiophen-3-yl (NHC(═O))₂NH₂- phenyl 2-chloro-phenyl H CH₃5-Cl-benzothiophen-3-yl 3-chloro-phenyl H CH₃ 5-Cl-benzothiophen-3-yl3,5-difluoro-phenyl H CH₃ 5-Cl-benzothiophen-3-yl 2,3-difluoro-phenyl HCH₃ 5-Cl-benzothiophen-3-yl 2-bromo-phenyl H CH₃ 5-Cl-benzothiophen-3-yl2,3-dimethoxy- H CH₃ 5-Cl-benzothiophen-3-yl phenyl 3-nitro-phenyl H CH₃5-Cl-benzothiophen-3-yl 3-bromo-phenyl H CH₃ 5-Cl-benzothiophen-3-yl3,5-dimethoxy- H CH₃ 5-Cl-benzothiophen-3-yl phenyl 2,5-difluoro-phenylH CH₃ 5-Cl-benzothiophen-3-yl 3,5-dichloro- H CH₃5-Cl-benzothiophen-3-yl phenyl 2,4-difluoro-phenyl H CH₃5-Cl-benzothiophen-3-yl 3-amino-phenyl H CH₃ 5-Cl-benzothiophen-3-ylphenyl —CH₂C(Me)₂CH₂O— naphthalen-1-yl phenyl 3-methoxy- OHnaphthalen-1-yl prop-1-yl phenyl 3-methoxy- 3-methoxy- naphthalen-1-ylprop-1-yl prop-1- yl-oxy phenyl 2-(1,3-dioxolan- OH naphthalen-1-yl2-yl)-eth-1-yl phenyl —CH₂OC(═O) OH naphthalen-1-yl t-butyl phenyl —CH₂CH₂ CH₂O— naphthalen-1-yl phenyl (2-dimethyl 2-dimethyl naphthalen-1-ylamino)- amino- eth-1-yl ethoxy phenyl —CH₂C(═O) —OCH₂ naphthalen-1-ylNEt₂ C(═O) NEt₂ phenyl —(CH₂)₂S —O(CH₂)₂S naphthalen-1-yl C(═O) C(═O)t-butyl t-butyl 3,4-difluoro-phenyl —CH₂OC(═O) CH₃5-Cl-benzothiophen-3-yl t-butyl 3,4-difluoro-phenyl (2-dimethyl CH₃5-Cl-benzothiophen-3-yl amino)- eth-1-yl 3,4-difluoro-phenyl (2-amino)-CH₃ 5-Cl-benzothiophen-3-yl eth-1-yl 3,4-difluoro-phenyl —CH₂O(═O) CH₃5-Cl-benzothiophen-3-yl NEt₂ 3,4-difluoro-phenyl —CH₂OC(═O) —OCH₂5-Cl-benzothiophen-3-yl t-butyl OC(═O) t-butyl 3,4-difluoro- —CH₂OC(═O)OH 5-Cl-benzothiophen-3-yl phenyl t-butyl 3,4-difluoro-phenyl —CH₂C(═O)—OCH₂ 5-Cl-benzothiophen-3-yl NEt₂ C(═O) N Et2 3,4-difluoro-phenyl —CH₂CH₂ CH₂O— 5-Cl-benzothiophen-3-yl 3,4-difluoro-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl methyl 3,4-difluoro-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl isopropyloxy 2-methoxy-phenyl H OH5-Cl-benzothiophen-3-yl pyridin-2-yl H OH 5-Cl-benzothiophen-3-yl3-trifluoromethoxy- H OH 5-Cl-benzothiophen-3-yl phenyl 3-methoxy-phenylH OH 5-Cl-benzothiophen-3-yl 2,6-difluoro-phenyl H OH5-Cl-benzothiophen-3-yl 2-chloro-phenyl H OH 5-Cl-benzothiophen-3-yl3-chloro-phenyl H OH 5-Cl-benzothiophen-3-yl 3,5-difluoro-phenyl H OH5-Cl-benzothiophen-3-yl 2,3-difluoro-phenyl H OH 5-Cl-benzothiophen-3-yl2-bromo-phenyl H OH 5-Cl-benzothiophen-3-yl 2,3-dimethoxy- H OH5-Cl-benzothiophen-3-yl phenyl 3-nitro-phenyl H OH5-Cl-benzothiophen-3-yl 3-bromo-phenyl H OH 5-Cl-benzothiophen-3-yl3,5-dimethoxy- H OH 5-Cl-benzothiophen-3-yl phenyl 2,5-difluoro-phenyl HOH 5-Cl-benzothiophen-3-yl 3,5-dichloro- H OH 5-Cl-benzothiophen-3-ylphenyl 2,4-difluoro-phenyl H OH 5-Cl-benzothiophen-3-yl 3-amino-phenyl HOH 5-Cl-benzothiophen-3-yl 2-methoxy-phenyl —CH₂OC(═O) t- CH₃5-Cl-benzothiophen-3-yl butyl pyridin-2-yl —CH₂OC(═O) t- CH₃5-Cl-benzothiophen-3-yl butyl 3-trifluoromethoxy- —CH₂OC(═O)t- CH₃5-Cl-benzothiophen-3-yl phenyl butyl 3-methoxy-phenyl —CH₂OC(═O) t- CH₃5-Cl-benzothiophen-3-yl butyl 2,6-difluoro-phenyl —CH₂OC(═O) t- CH₃5-Cl-benzothiophen-3-yl butyl 2-chloro-phenyl —CH₂OC(═O) t- CH₃5-Cl-benzothiophen-3-yl butyl 3-chloro-phenyl —CH₂OC(═O) t- CH₃5-Cl-benzothiophen-3-yl butyl 3,5-difluoro-phenyl —CH₂OC(═O) t- CH₃5-Cl-benzothiophen-3-yl butyl 2,3-difluoro-phenyl —CH₂OC(═O) t- CH₃5-Cl-benzothiophen-3-yl butyl 2-bromo-phenyl —CH₂OC(═O) t- CH₃5-Cl-benzothiophen-3-yl butyl 2,3-dimethoxy- —CH₂OC(═O) t- CH₃5-Cl-benzothiophen-3-yl phenyl butyl 3-nitro-phenyl —CH₂OC(═O) t- CH₃5-Cl-benzothiophen-3-yl butyl 3-bromo-phenyl —CH₂OC(═O) t- CH₃5-Cl-benzothiophen-3-yl butyl 3,5-dimethoxy- —CH₂OC(═O) t- CH₃5-Cl-benzothiophen-3-yl phenyl butyl 2,5-difluoro-phenyl —CH₂OC(═O) t-CH₃ 5-Cl-benzothiophen-3-yl butyl 3,5-dichloro- —CH₂OC(═O) t- CH₃5-Cl-benzothiophen-3-yl phenyl butyl 2,4-difluoro-phenyl —CH₂OC(═O) t-CH₃ 5-Cl-benzothiophen-3-yl butyl 3-amino-phenyl —CH₂OC(═O) t- CH₃5-Cl-benzothiophen-3-yl butyl 2-methoxy-phenyl —CH₂OC(═O) —OCH₂5-Cl-benzothiophen-3-yl t-butyl OC(═O) t-butyl pyridin-2-yl —CH₂OC(═O)—OCH₂ 5-Cl-benzothiophen-3-yl t-butyl OC(═O) t-butyl 3-trifluoromethoxy-—CH₂OC(═O) —OCH₂ 5-Cl-benzothiophen-3-yl phenyl t-butyl OC(═O) t-butyl3-methoxy-phenyl —CH₂OC(═O) —OCH₂ 5-Cl-benzothiophen-3-yl t-butyl OC(═O)t-butyl 2,6-difluoro-phenyl —CH₂OC(═O) —OCH₂ 5-Cl-benzothiophen-3-ylt-butyl OC(═O) t-butyl 2-chloro-phenyl —CH₂OC(═O) —OCH₂5-Cl-benzothiophen-3-yl t-butyl OC(═O) t-butyl 3-chloro-phenyl—CH₂OC(═O) —OCH₂ 5-Cl-benzothiophen-3-yl t-butyl OC(═O) t-butyl3,5-difluoro-phenyl —CH₂OC(═O) —OCH₂ 5-Cl-benzothiophen-3-yl t-butylOC(═O) t-butyl 2,3-difluoro-phenyl —CH₂OC(═O) —OCH₂5-Cl-benzothiophen-3-yl t-butyl OC(═O) t-butyl 2-bromo-phenyl —CH₂OC(═O)—OCH₂ 5-Cl-benzothiophen-3-yl t-butyl OC(═O) t-butyl 2,3-dimethoxy-—CH₂OC(═O) —OCH₂ 5-Cl-benzothiophen-3-yl phenyl t-butyl OC(═O) t-butyl3-nitro-phenyl —CH₂OC(═O) —OCH₂ 5-Cl-benzothiophen-3-yl t-butyl OC(═O)t-butyl 3-bromo-phenyl —CH₂OC(═O) —OCH₂ 5-Cl-benzothiophen-3-yl t-butylOC(═O) t-butyl 3,5-dimethoxy- —CH₂OC(═O) —OCH₂ 5-Cl-benzothiophen-3-ylphenyl t-butyl OC(═O) t-butyl 2,5-difluoro-phenyl —CH₂OC(═O) —OCH₂5-Cl-benzothiophen-3-yl t-butyl OC(═O) t-butyl 3,5-dichloro- —CH₂OC(═O)—OCH₂ 5-Cl-benzothiophen-3-yl phenyl t-butyl OC(═O) t-butyl2,4-difluoro-phenyl —CH₂OC(═O) —OCH₂ 5-Cl-benzothiophen-3-yl t-butylOC(═O) t-butyl 3-amino-phenyl —CH₂OC(═O) —OCH₂ 5-Cl-benzothiophen-3-ylt-butyl OC(═O) t-butyl 2-methoxy-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl t-butyl pyridin-2-yl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl t-butyl 3-trifluoromethoxy- —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl phenyl t-butyl 3-methoxy-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl t-butyl 2,6-difluoro-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl t-butyl 2-chloro-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl t-butyl 3-chloro-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl t-butyl 3,5-difluoro-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl t-butyl 2,3-difluoro-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl t-butyl 2-bromo-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl t-butyl 2,3-dimethoxy- —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl phenyl t-butyl 3-nitro-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl t-butyl 3-bromo-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl t-butyl 3,5-dimethoxy- —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl phenyl t-butyl 2,5-difluoro-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl t-butyl 3,5-dichloro- —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl phenyl t-butyl 2,4-difluoro-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl t-butyl 3-amino-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl t-butyl 2-methoxy-phenyl —CH₂ CH₂ CH₂O—5-Cl-benzothiophen-3-yl pyridin-2-yl —CH₂ CH₂ CH₂O—5-Cl-benzothiophen-3-yl 3-trifluoromethoxy- —CH₂ CH₂ CH₂O—5-Cl-benzothiophen-3-yl phenyl 3-methoxy-phenyl —CH₂ CH₂ CH₂O—5-Cl-benzothiophen-3-yl 2,6-difluoro-phenyl —CH₂ CH₂ CH₂O—5-Cl-benzothiophen-3-yl 2-chloro-phenyl —CH₂ CH₂ CH₂O—5-Cl-benzothiophen-3-yl 3-chloro-phenyl —CH₂ CH₂ CH₂O—5-Cl-benzothiophen-3-yl 3,5-difluoro-phenyl —CH₂ CH₂ CH₂O—5-Cl-benzothiophen-3-yl 2,3-difluoro-phenyl —CH₂ CH₂ CH₂O—5-Cl-benzothiophen-3-yl 2-bromo-phenyl —CH₂ CH₂ CH₂O—5-Cl-benzothiophen-3-yl 2,3-dimethoxy- —CH₂ CH₂ CH₂O—5-Cl-benzothiophen-3-yl phenyl 3-nitro-phenyl —CH₂ CH₂ CH₂O—5-Cl-benzothiophen-3-yl 3-bromo-phenyl —CH₂ CH₂ CH₂O—5-Cl-benzothiophen-3-yl 3,5-dimethoxy- —CH₂ CH₂ CH₂O—5-Cl-benzothiophen-3-yl phenyl 2,5-difluoro-phenyl —CH₂ CH₂ CH₂O—5-Cl-benzothiophen-3-yl 3,5-dichloro- —CH₂ CH₂ CH₂O—5-Cl-benzothiophen-3-yl phenyl 2,4-difluoro-phenyl —CH₂ CH₂ CH₂O—5-Cl-benzothiophen-3-yl 3-amino-phenyl —CH₂ CH₂ CH₂O—5-Cl-benzothiophen-3-yl 2-methoxy-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl isopropyloxy pyridin-2-yl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl isopropyloxy 3-trifluoromethoxy- —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl phenyl isopropyloxy 3-methoxy-phenyl —CH₂OC(═O)OH 5-Cl-benzothiophen-3-yl isopropyloxy 2,6-difluoro-phenyl —CH₂OC(═O)OH 5-Cl-benzothiophen-3-yl isopropyloxy 2-chloro-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl isopropyloxy 3-chloro-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl isopropyloxy 3,5-difluoro-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl isopropyloxy 2,3-difluoro-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl isopropyloxy 2-bromo-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl isopropyloxy 2,3-dimethoxy- —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl phenyl isopropyloxy 3-nitro-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl isopropyloxy 3-bromo-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl isopropyloxy 3,5-dimethoxy- —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl phenyl isopropyloxy 2,5-difluoro-phenyl—CH₂OC(═O) OH 5-Cl-benzothiophen-3-yl isopropyloxy 3,5-dichloro-—CH₂OC(═O) OH 5-Cl-benzothiophen-3-yl phenyl isopropyloxy2,4-difluoro-phenyl —CH₂OC(═O) OH 5-Cl-benzothiophen-3-yl isopropyloxy3-amino-phenyl —CH₂OC(═O) OH 5-Cl-benzothiophen-3-yl isopropyloxy3-fluoro-5-chloro- H CH₃ 5-Cl-benzothiophen-3-yl phenyl2-fluoro-3-chloro- H CH₃ 5-Cl-benzothiophen-3-yl phenyl4-fluoro-3-chloro- H CH₃ 5-Cl-benzothiophen-3-yl phenyl2-fluoro-5-chloro- H CH₃ 5-Cl-benzothiophen-3-yl phenyl 3,5-dibromo- HCH₃ 5-Cl-benzothiophen-3-yl phenyl 3-cyano-phenyl H CH₃5-Cl-benzothiophen-3-yl 2-cyano-phenyl H CH₃ 5-Cl-benzothiophen-3-yl3-fluoro-5- H CH₃ 5-Cl-benzothiophen-3-yl trifluoromethyl- phenyl3-fluoro-5-chloro- H OH 5-Cl-benzothiophen-3-yl phenyl2-fluoro-3-chloro- H OH 5-Cl-benzothiophen-3-yl phenyl4-fluoro-3-chloro- H OH 5-Cl-benzothiophen-3-yl phenyl2-fluoro-5-chloro- H OH 5-Cl-benzothiophen-3-yl phenyl 3,5-dibromo- H OH5-Cl-benzothiophen-3-yl phenyl 3-cyano-phenyl H OH5-Cl-benzothiophen-3-yl 2-cyano-phenyl H OH 5-Cl-benzothiophen-3-yl3-fluoro-5- H OH 5-Cl-benzothiophen-3-yl trifluoromethyl- phenyl3-fluoro-5-chloro- —CH₂OC(═O) t- CH₃ 5-Cl-benzothiophen-3-yl phenylbutyl 2-fluoro-3-chloro- —CH₂OC(═O) t- CH₃ 5-Cl-benzothiophen-3-ylphenyl butyl 4-fluoro-3-chloro- —CH₂OC(═O) t- CH₃5-Cl-benzothiophen-3-yl phenyl butyl 2-fluoro-5-chloro- —CH₂OC(═O) t-CH₃ 5-Cl-benzothiophen-3-yl phenyl butyl 3,5-dibromo- —CH₂OC(═O) t- CH₃5-Cl-benzothiophen-3-yl phenyl butyl 3-cyano-phenyl —CH₂OC(═O) t- CH₃5-Cl-benzothiophen-3-yl butyl 2-cyano-phenyl —CH₂OC(═O) t- CH₃5-Cl-benzothiophen-3-yl butyl 3-fluoro-5- —CH₂OC(═O) t- CH₃5-Cl-benzothiophen-3-yl trifluoromethyl- butyl phenyl 3-fluoro-5-chloro-—CH₂OC(═O) —OCH₂ 5-Cl-benzothiophen-3-yl phenyl t-butyl OC(═O) t-butyl2-fluoro-3-chloro- —CH₂OC(═O) —OCH₂ 5-Cl-benzothiophen-3-yl phenylt-butyl OC(═O) t-butyl 4-fluoro-3-chloro- —CH₂OC(═O) —OCH₂5-Cl-benzothiophen-3-yl phenyl t-butyl OC(═O) t-butyl 2-fluoro-5-chloro-—CH₂OC(═O) —OCH₂ 5-Cl-benzothiophen-3-yl phenyl t-butyl OC(═O) t-butyl3,5-dibromo- —CH₂OC(═O) —OCH₂ 5-Cl-benzothiophen-3-yl phenyl t-butylOC(═O) t-butyl 3-cyano-phenyl —CH₂OC(═O) —OCH₂ 5-Cl-benzothiophen-3-ylt-butyl OC(═O) t-butyl 2-cyano-phenyl —CH₂OC(═O) —OCH₂5-Cl-benzothiophen-3-yl t-butyl OC(═O) t-butyl 3-fluoro-5- —CH₂OC(═O)—OCH₂ 5-Cl-benzothiophen-3-yl trifluoromethyl- t-butyl OC(═O) phenylt-butyl 3-fluoro-5-chloro- —CH₂OC(═O) OH 5-Cl-benzothiophen-3-yl phenylt-butyl 2-fluoro-3-chloro- —CH₂OC(═O) OH 5-Cl-benzothiophen-3-yl phenylt-butyl 4-fluoro-3-chloro- —CH₂OC(═O) OH 5-Cl-benzothiophen-3-yl phenylt-butyl 2-fluoro-5-chloro- —CH₂OC(═O) OH 5-Cl-benzothiophen-3-yl phenylt-butyl 3,5-dibromo- —CH₂OC(═O) OH 5-Cl-benzothiophen-3-yl phenylt-butyl 3-cyano-phenyl —CH₂OC(═O) OH 5-Cl-benzothiophen-3-yl t-butyl2-cyano-phenyl —CH₂OC(═O) OH 5-Cl-benzothiophen-3-yl t-butyl 3-fluoro-5-—CH₂OC(═O) OH 5-Cl-benzothiophen-3-yl trifluoromethyl- t-butyl phenyl3-fluoro-5-chloro- —CH₂ CH₂ CH₂O— 5-Cl-benzothiophen-3-yl phenyl2-fluoro-3-chloro- —CH₂ CH₂ CH₂O— 5-Cl-benzothiophen-3-yl phenyl4-fluoro-3-chloro- —CH₂ CH₂ CH₂O— 5-Cl-benzothiophen-3-yl phenyl2-fluoro-5-chloro- —CH₂ CH₂ CH₂O— 5-Cl-benzothiophen-3-yl phenyl3,5-dibromo- —CH₂ CH₂ CH₂O— 5-Cl-benzothiophen-3-yl phenyl3-cyano-phenyl —CH₂ CH₂ CH₂O— 5-Cl-benzothiophen-3-yl 2-cyano-phenyl—CH₂ CH₂ CH₂O— 5-Cl-benzothiophen-3-yl 3-fluoro-5- —CH₂ CH₂ CH₂O—5-Cl-benzothiophen-3-yl trifluoromethyl- phenyl 3-fluoro-5-chloro-—CH₂OC(═O) OH 5-Cl-benzothiophen-3-yl phenyl isopropyloxy2-fluoro-3-chloro- —CH₂OC(═O) OH 5-Cl-benzothiophen-3-yl phenylisopropyloxy 4-fluoro-3-chloro- —CH₂OC(═O) OH 5-Cl-benzothiophen-3-ylphenyl isopropyloxy 2-fluoro-5-chloro- —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl phenyl isopropyloxy 3,5-dibromo- —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl phenyl isopropyloxy 3-cyano-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl isopropyloxy 2-cyano-phenyl —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl isopropyloxy 3-fluoro-5- —CH₂OC(═O) OH5-Cl-benzothiophen-3-yl trifluoromethyl- isopropyloxy phenyl

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (I) selected from the groupconsisting of:

In another embodiment, the present invention is directed to a processfor the preparation of a compound of formula (I) selected from the groupconsisting of:

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (I) wherein ring A, R², R³, R⁵, R⁶,Z, and R⁴ are selected from the group consisting of:

Formula

R⁵ R⁶ Z-R⁴ (I-A) 3,4-difluoro- H CH₃ 5-chloro-benzo- phenylthiophen-3-yl (I-B) 3,4-difluoro- H OH 5-chloro-benzo- phenylthiophen-3-yl (I-C) 3,4-difluoro- —CH₂OC(O)- OH 5-chloro-benzo- phenylt-butyl thiophen-3-yl (I-D) 3,4-difluoro- —CH₂OC(O)— OH 5-chloro-benzo-phenyl isopropyloxy thiophen-3-yl (I-E) 3,5-dichloro- H CH₃5-chloro-benzo- phenyl thiophen-3-yl (I-F) 3,5-dichloro- H OH5-chloro-benzo- phenyl thiophen-3-yl (I-G) 3,5-dichloro- —CH₂OC(O)- OH5-chloro-benzo- phenyl t-butyl thiophen-3-yl (I-H) 3,5-dichloro-—CH₂OC(O)— OH 5-chloro-benzo- phenyl isopropyloxy thiophen-3-yl.

In yet another embodiment, the present invention is directed to aprocess for the preparation of a compound of formula (I) selected fromthe group consisting of

As used herein, unless otherwise noted, “alkyl” whether used alone or aspart of a substituent group refers to straight and branched carbonchains having 1 to 8 carbon atoms or any number within this range. Theterm “alkoxy” refers to an —Oalkyl substituent group, wherein alkyl isas defined supra. Similarly, the terms “alkenyl” and “alkynyl” refer tostraight and branched carbon chains having 2 to 8 carbon atoms or anynumber within this range, wherein an alkenyl chain has at least onedouble bond in the chain and an alkynyl chain has at least one triplebond in the chain. An alkyl and alkoxy chain may be substituted on aterminal carbon atom or, when acting as a linking group, within thecarbon chain.

The term “cycloalkyl” refers to saturated or partially unsaturated,moncyclic or polycyclic hydrocarbon rings of from 3 to 20 carbon atommembers (preferably from 3 to 14 carbon atom members). Further, acycloalkyl ring may optionally be fused to one or more cycloalkyl rings.Examples of such rings include, and are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.

The term “heterocyclyl” refers to a nonaromatic cyclic ring of 5 to 10members in which 1 to 4 members are nitrogen or a nonaromatic cyclicring of 5 to 10 members in which zero, one or two members are nitrogenand up to two members is oxygen or sulfur; wherein, optionally, the ringcontains zero, one or two unsaturated bonds. Alternatively, theheterocyclyl ring may be fused to a benzene ring (benzo fusedheterocyclyl), a 5 or 6 membered heteroaryl ring (containing one of O, Sor N and, optionally, one additional nitrogen), a 5 to 7 memberedcycloalkyl or cycloalkenyl ring, a 5 to 7 membered heterocyclyl ring (ofthe same definition as above but absent the option of a further fusedring) or fused with the carbon of attachment of a cycloalkyl,cycloalkenyl or heterocyclyl ring to form a spiro moiety. For instantcompounds of the invention, the carbon atom ring members that form theheterocyclyl ring are fully saturated. Other compounds of the inventionmay have a partially saturated heterocyclyl ring. Additionally, theheterocyclyl can be bridged to form bicyclic rings. Preferred partiallysaturated heterocyclyl rings may have from one to two double bonds. Suchcompounds are not considered to be fully aromatic and are not referredto as heteroaryl compounds. Examples of heterocyclyl groups include, andare not limited to, pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl or3-pyrrolinyl), pyrrolidinyl, 2-imidazolinyl, imidazolidinyl,2-pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,and piperazinyl.

The term “aryl” refers to an unsaturated, aromatic monocyclic ring of 6carbon members or to an unsaturated, aromatic polycyclic ring of from 10to 20 carbon members. Examples of such aryl rings include, and are notlimited to, phenyl, naphthalenyl and anthracenyl. Preferred aryl groupsfor the practice of this invention are phenyl and naphthalenyl.

The term “benzo fused cycloalkyl” refers to a bicyclic or tricyclic ringstructure wherein at least one of the ring substituents is phenyl ornaphthalenyl and at least one of the other substituents is a cycloalkylring (as cycloalkyl was previously defined). For the purpose of thesedefinitions, the cycloalkyl rings may be fused to an additional benzenering (to provide fused multiple ring systems such as fluorene). Exampleof such benzo fused cycloalkyls include, but are not limited to,indanyl, 1,2,3,4-tetrahydronaphthalenyl and fluorenyl.

The term “heteroaryl” refers to an aromatic ring of 5 or 6 memberswherein the ring consists of carbon atoms and has at least oneheteroatom member. Suitable heteroatoms include nitrogen, oxygen orsulfur. In the case of 5 membered rings, the heteroaryl ring containsone member of nitrogen, oxygen or sulfur and, in addition, may containup to three additional nitrogens. In the case of 6 membered rings, theheteroaryl ring may contain from one to three nitrogen atoms. For thecase wherein the 6 membered ring has three nitrogens, at most twonitrogen atoms are adjacent. Optionally, the heteroaryl ring is fused toa benzene ring (benzo fused heteroaryl), a 5 or 6 membered heteroarylring (containing one of O, S or N and, optionally, one additionalnitrogen), a 5 to 7 membered cycloalkyl ring or a 5 to 7 memberedheterocyclo ring (as defined supra but absent the option of a furtherfused ring). Examples of heteroaryl groups include, and are not limitedto, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl; fusedheteroaryl groups include indolyl, isoindolyl, indolinyl, benzofuryl,benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,benzisoxazolyl, benzothiadiazolyl, benzotriazolyl, quinolizinyl,quinolinyl, isoquinolinyl, and quinazolinyl.

The term “arylalkyl” means an alkyl group substituted with an aryl group(e.g., benzyl and phenethyl). Similarly, the term “arylalkoxy” indicatesan alkoxy group substituted with an aryl group (e.g., benzyloxy).

The term “halogen” refers to fluorine, chlorine, bromine, and iodine.Substituents that are substituted with multiple halogens are substitutedin a manner that provides compounds which are stable.

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappear in a name of a substituent (e.g., arylalkyl and alkylamino), itshall be interpreted as including those limitations given above for“alkyl” and “aryl.” Designated numbers of carbon atoms (e.g., C₁-C₆)shall refer independently to the number of carbon atoms in an alkylmoiety or to the alkyl portion of a larger substituent in which alkylappears as its prefix root. For alkyl, and alkoxy substituents thedesignated number of carbon atoms includes all of the independent memberincluded in the range specified individually and all the combination ofranges within in the range specified. For example C₁₋₆ alkyl wouldinclude methyl, ethyl, propyl, butyl, pentyl and hexyl individually aswell as sub-combinations thereof (e.g., C₁₋₂, C₁₋₃, C₁₋₄, C₁₋₅, C₂₋₆,C₃₋₆, C₄₋₆, C₅₋₆, C₂₋₅, etc.). However, for clarity in the terms “C₉-C₁₄benzo fused cycloalkyl”, “C₉-C₁₄ benzo fused cycloalkenyl”, “C₉-C₁₄benzo fused aryl”; C₉-C₁₄ refers to the number of carbon atoms both inthe benzene ring (6) and the number of atoms in the ring fused to thebenzene ring, but does not include carbon atoms that may be pendent fromthese multiple ring systems. The amount of substituents attached to amoiety “optionally substituted with one to five substituents” is limitedto that amount of open valences on the moiety available forsubstitution.

When a particular group is “substituted” (e.g., alkkyl, cycloalkyl,aryl, heteroaryl, heterocycloalkyl, etc.), that group may have one ormore substituents, preferably from one to five substituents, morepreferably from one to three substituents, most preferably from one totwo substituents, independently selected from the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

As used herein, the notation “*” shall denote the presence of astereogenic center.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Preferably, wherein the compound is present as an enantiomer, theenantiomer is present at an enantiomeric excess of greater than or equalto about 80%, more preferably, at an enantiomeric excess of greater thanor equal to about 90%, more preferably still, at an enantiomeric excessof greater than or equal to about 95%, more preferably still, at anenantiomeric excess of greater than or equal to about 98%, mostpreferably, at an enantiomeric excess of greater than or equal to about99%. Similarly, wherein the compound is present as a diastereomer, thediastereomer is present at an diastereomeric excess of greater than orequal to about 80%, more preferably, at an diastereomeric excess ofgreater than or equal to about 90%, more preferably still, at andiastereomeric excess of greater than or equal to about 95%, morepreferably still, at an diastereomeric excess of greater than or equalto about 98%, most preferably, at an diastereomeric excess of greaterthan or equal to about 99%.

Similarly, wherein a compound of the present invention comprises one ormore double bonds, said double bond(s) may each be independently presentin a cis or trans configuration (also sometimes referred to as in an “Z”or “E” configurations, respectively). It is to be understood that cisand trans geometric isomers and all mixtures thereof are encompassedwithin the scope of the present invention. Wherein a compound comprisinga single double bound is present in an excess of one of itscorresponding geometric isomers (for example, in an excess of itscorresponding trans isomer), said compound is preferably present suchthat the desired geometric isomer is present in amount of greater thanabout 50%, Further, more preferably, greater than about 75%, morepreferably, greater than about 90%, more preferably, greater than about95%, most preferably, greater than about 99%.

Furthermore, some of the crystalline forms for the compounds of thepresent invention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe present invention may form solvates with water (i.e., hydrates) orcommon organic solvents, and such solvates are also intended to beencompassed within the scope of this invention.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylC₁-C₆alkylaminocarbonylC₁-C₆alkyl”substituent refers to a group of the formula

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows

DCE=Dichloroethane

DCM=Dichloromethane

DIPEA or DIEA=Diisopropylethylamine

DMA or DMAc=N,N-Dimethylacetamide

DME=1,2-Dimethoxyethane

DMF=N,N-Dimethylformamide

EtOAc=Ethyl acetate

HPLC=High Pressure Liquid Chromatography

LiHMDS=Lithium bis(trimethylsilyl)amide

Mn(OAc)₂=Manganese Acetate

MTBE=Methyl t-Butyl Ether

NaHMDS=Sodium bis(trimethylsilyl)amide

NBS=N-bromosuccinimide

NMP=N-methyl-2-pyrrolidinone

NH₄OAc=Ammonium Acetate

TEA=Triethylamine

THF=Tetrahydrofuran

TLC=Thin Layer Chromatography

TMS-Br=Bromotrimethylsilane

TMS-Cl=Chlorotrimethylsilane

TMS-I=Iodotrimethylsilane

As used herein, unless otherwise noted, the term “isolated form” shallmean that the compound is present in a form which is separate from anysolid mixture with another compound(s), solvent system or biologicalenvironment. In an embodiment of the present invention, the compound offormula (I) is prepared as an isolated form. In additional embodimentsof the present invention, the compound of formula (I-A), (I-B), (I-C),(I-D), (I-E), (I-F), (I-G) and/or (I-H) is prepared as an isolated form.

As used herein, unless otherwise noted, the term “substantially pureform” shall mean that the mole percent of impurities in the isolatedcompound is less than about 5 mole percent, preferably less than about 2mole percent, more preferably, less than about 0.5 mole percent, mostpreferably, less than about 0.1 mole percent. In an embodiment of thepresent invention, the compound of formula (I) is prepared as asubstantially pure form. In additional embodiments of the presentinvention, the compounds of formula (I-A), (I-B), (I-C), (I-D), (I-E),(I-F), (I-G) and/or (I-H) is prepared as a substantially pure form.

As used herein, unless otherwise noted, the term “substantially free ofa corresponding salt form(s)” when used to described the compound offormula (I) shall mean that mole percent of the corresponding saltform(s) in the isolated base of formula (I) is less than about 5 molepercent, preferably less than about 2 mole percent, more preferably,less than about 0.5 mole percent, most preferably less than about 0.1mole percent. In an embodiment of the present invention, the compound offormula (I) is prepared in a form which is substantially free ofcorresponding salt form(s). In additional embodiments of the presentinvention, the compound of formula (I-A), (I-B), (I-C), (I-D), (I-E),(I-F), (I-G) and/or (I-H) is prepared in a form which is substantiallyfree of corresponding salt form(s).

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment. Preferably, the subject has experiencedand/or exhibited at least one symptom of the disease or disorder to betreated and/or prevented.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

The compounds of formula (I) (disclosed as in U.S. Pat. No. 7,459,444,issued Dec. 2, 2008, which is incorporated by reference herein in itsentirety), prepared according to the process of the present invention,are useful serine protease inhibitors (in particular, inhibitors ofchymase) useful for treating inflammatory, and serine protease mediateddisorders. Serine proteases such as chymase produced by mast cells havebeen recognized to be involved in a variety of inflammatory and woundhealing events (e.g., angiogenesis, collagen deposition and cellproliferation). Chymase plays these roles by activating a variety ofpre-existing factors present in the microenvironment surrounding themast cells. For example, just to name a few of these interactionschymase activates SCF, angiotensin Ito angiotensin II, endothelin 1,type 1 procollagen, metalloprotienases, IL-1B, TGF-β, as well as,degrades the extracellular matrix (de Paulis et al. Int Arch AllergImmunol 118 (1999) 422-425; Longley et al. Proc Natl Acad Sci USA 94(1997) 9017-9021). Consequently, the release of chymase playssignificant role in a variety of pathological conditions associated withvascular proliferation, fibrosis, tissue remodeling, inflammation, andthe like.

Some of these, inflammatory and serine protease mediated disordersinclude, and are not limited to, allergic rhinitis, viral rhinitis,asthma, chronic obstructive pulmonary diseases, bronchitis, pulmonaryemphysema, acute lung injury (e.g. adult (acute) respiratory distresssyndrome), psoriasis, arthritis, reperfusion injury, ischemia,hypertension, hypercardia, myocardial infarction, heart failure damageassociated with myocardial infarction, cardiac hypertrophy,arteriosclerosis, saroidosis, vascular stenosis or restenosis (e.g.,associated with vascular injury, angioplasty, vascular stents orvascular grafts), pulmonary fibrosis, kidney fibrosis (e.g., associatedwith glomerulonephritis), liver fibrosis, post surgical adhesionformation, systemic sclerosis, keloid scars rheumatoid arthritis,bullous pemphigiod and atherosclerosis. Additionally, these compoundscan be used for modulating wound healing and remodeling (e.g., cardiachypertrophy) as well as immune modulation.

One skilled in the art will recognize that, where not otherwisespecified, the reaction step(s) is performed under suitable conditions,according to known methods, to provide the desired product.

One skilled in the art will recognize that, in the specification andclaims as presented herein, wherein a substituent group (e.g. protectinggroup such as PG¹ or PG²; activating group such as Y¹; leaving groupsuch as Q¹; alkyl substituent such as A¹; etc.) or reagent or reagentclass/type (e.g. base, solvent, etc.) is recited in more than one stepof a process, or in more than one process, the individual substituentgroups and reagents are independently selected for each reaction stepand may be the same of different from each other. For example whereintwo steps of a process recite an organic or inorganic base as a reagent,the organic or inorganic base selected for the first step may be thesame or different than the organic or inorganic base of the second step.

To provide a more concise description, some of the quantitativeexpressions herein are recited as a range from about amount X to aboutamount Y. It is understood that wherein a range is recited, the range isnot limited to the recited upper and lower bounds, but rather includesthe full range from about amount X through about amount Y, or any rangetherein.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

As used herein, unless otherwise noted, the term “aprotic solvent” shallmean any solvent that does not yield a proton. Suitable examplesinclude, but are not limited to DMF, 1,4-dioxane, THF, acetonitrile,pyridine, dichloroethane, dichloromethane, MTBE, toluene, acetone, andthe like.

As used herein, unless otherwise noted, the term “leaving group” shallmean a charged or uncharged atom or group which departs during asubstitution or displacement reaction. Suitable examples include, butare not limited to, Br, Cl, I, mesylate, tosylate, and the like.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

One skilled in the art will recognize that in the processes as describedherein it may be advantageous and/or desirable to protected terminalsubstituent groups such as hydroxy, alkoxy, alkylcarbonyloxy,alkoxycarbonyloxy, and the like.

As used herein, unless otherwise noted, the term “nitrogen protectinggroup” shall mean a group which may be attached to a nitrogen atom toprotect said nitrogen atom from participating in a reaction and whichmay be readily removed following the reaction. Suitable nitrogenprotecting groups include, but are not limited to carbamates—groups ofthe formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl,benzyl, phenylethyl, CH₂═CH—CH₂—, and the like; amides—groups of theformula —C(O)—R′ wherein R′ is for example methyl, phenyl,trifluoromethyl, and the like; N-sulfonyl derivatives—groups of theformula —SO₂—R″ wherein R″ is for example tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogenprotecting groups may be found in texts such as T. W. Greene & P. G. M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

As used herein, unless otherwise noted, the term “oxygen protectinggroup” shall mean a group which may be attached to a oxygen atom toprotect said oxygen atom from participating in a reaction and which maybe readily removed following the reaction. Suitable oxygen protectinggroups include, but are not limited to, acetyl, benzoyl,t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, THP, and the like.Other suitable oxygen protecting groups may be found in texts such as T.W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991.

One skilled in the art will recognize that wherein a reaction step ofthe present invention may be carried out in a variety of solvents orsolvent systems, said reaction step may also be carried out in a mixtureof the suitable solvents or solvent systems.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

The processes of the present invention may be used in the preparation ofcompounds which act as prodrugs of the compounds of formula (I). Ingeneral, such prodrugs will be functional derivatives of the compoundswhich are readily convertible in vivo into the required pharmaceuticallyactive compound. Thus, in the methods of treatment of the presentinvention, the term “administering” shall encompass the treatment of thevarious disorders described with the compound specifically disclosed orwith a compound which may not be specifically disclosed, but whichconverts to the specified pharmaceutically active compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts include,but are not limited to, the following: acetate, benzenesulfonate,benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calciumedetate, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate(embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

Representative acids which may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, thefollowing: acids including acetic acid, 2,2-dichloroacetic acid,acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaricacid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronicacid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hipuric acid,hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lacticacid, lactobionic acid, maleic acid, (−)-L-malic acid, malonic acid,(±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotincacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid,4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid,sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid,p-toluenesulfonic acid and undecylenic acid.

Representative bases which may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, thefollowing: bases including ammonia, L-arginine, benethamine, benzathine,calcium hydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

The present invention is directed to a process for the preparation of acompound of formula (III), as outlined in more detail in Scheme 1, whichfollows herein. The compound of formula (III) is useful as anintermediate in the synthesis of, for example, a compound of formula(I-A), a compound of formula (I-B), a compound of formula (I-C) and/or acompound of formula (I-D).

In some embodiments, the present invention is directed to processes forthe preparation of compounds of formula (L), more particularly toprocess for the preparation of compounds of formula (IX) and compoundsof formula (XV), as described in more detail in Schemes 2 through 5,which follow herein. The compounds of formula (L), and more particularlythe compounds of formula (IX) and the compounds of formula (XV), areuseful as intermediates in the synthesis of compounds of formula (I).

In some embodiments, the present invention is directed to processes forthe preparation of the compounds of formula (I), as described in moredetail in Schemes 6 through 9, which follow herein. The compounds offormula (I) are useful as chymase modulators, as described in moredetail herein. In additional embodiments, the present invention isdirected to processes for the preparation of the compounds of formula(I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G) and (I-H), as describedin more detail in Schemes 10 through 17, which follow herein.

The present invention is directed to a process for the preparation of acompound of formula (III), as outlined in Scheme 1, below.

Accordingly, a suitably substituted compound of formula (II), a knowncompound or compound prepared by known methods, wherein the compound offormula (II) is preferably present in an excess of its correspondingtrans form, more preferably present as its corresponding trans form; isreacted with a suitably selected brominating agent such as1-bromo-pyrrolidine-2,5-dione, bromine gas, dibromohydantoin, and thelike, preferably, 1-bromo-pyrrolidine-2,5-dione; wherein the brominatingagent is preferably present in an amount in the range of from about 0.5to about 2.0 molar equivalents (relative to the moles of the compound offormula (II), more preferably in an amount in the range of from about0.8 to about 1.2 molar equivalents, more preferably still in an amountof about 1.1 molar equivalents;

in the presence of a suitably selected catalyst such as lithium acetate,manganese acetate hydrate, magnesium acetate, and the like, preferablymanganese acetate hydrate; wherein the catalyst is preferably present inan amount in the range of from about 0.2 to about 1.0 molar equivalents(relative to the moles of the compound of formula (II), more preferablyin an amount in the range of from about 0.3 to about 0.8 molarequivalents, more preferably still in an amount of about 0.5 molarequivalents;

in a mixture of water and an organic solvent such as acetonitrile, THF,and the like, preferably acetonitrile; preferably at a temperature inthe range of from about 25° C. to about 70° C.; to yield thecorresponding compound of formula (III).

The present invention is further directed to processes for thepreparation of compounds of formula (IX) as outlined in Scheme 2, below.

Accordingly, a suitably substituted compound of formula (IV), a knowncompound or compound prepared by known methods, wherein PG¹ is asuitably selected oxygen protecting group such as C₁₋₄alkyl, and thelike, preferably PG¹ is methyl, ethyl or t-butyl, more preferably, PG¹is ethyl, is reacted with a suitably selected source of nitrogen such asLiHMDS, NaHMDS, and the like, preferably LiHMDS; wherein the source ofnitrogen is preferably present in an amount in the range of from about3.0 to about 6.0 molar equivalents, preferably about 3.0 molarequivalents;

in the presence of CO₂ gas; wherein the CO₂ gas is preferably bubbledinto the reaction mixture in an excess amount; in an organic solventsuch as THF, MTBE, DME, glyme, and the like; preferably THF; preferablyat a temperature in the range of from about −10° C. to about 20° C.,more preferably at a temperature in the range of from about 0° C. toabout 20° C.; to yield the corresponding compound of formula (IX).

One skilled in the art will recognize that in the process as describedabove, the compound of formula (IX) is prepared in a mixture with thecorresponding acid (a compound of formula (V)). Preferably, the compoundof formula (IX) is isolated and/or further purified according to knownmethods, for example, the compound of formula (IX) may be furtherpurified by acid/base workup.

Alternatively, a suitably substituted compound of formula (IV), a knowncompound or compound prepared by known methods is reacted with carbondioxide; wherein the carbon dioxide is preferably bubbled into thereaction mixture in an excess amount, for example in an amount in therange of from about 10 to about 20 molar equivalents;

in the presence of a base such as n-butyl lithium, hexyl-lithium, andthe like, preferably n-butyl lithium, wherein the base is preferablypresent in an amount in the range of from about 2.0 to bout 6.0 molarequivalents, more preferably about 3.0 molar equivalents; in an organicsolvent or mixture thereof such as THF, THF/toluene, MTBE, and the like,preferably THF; preferably at a temperature in the range of from about−78° C. to about −40° C.; to yield the corresponding compound of formula(V).

The compound of formula (V) is reacted according to any of Methods Athrough C as outlined in more detail below, to yield the correspondingcompound of formula (X). More particularly, as shown briefly below

the compound of formula (V) is activated to yield the correspondingcompound of formula (A1), wherein Y¹ is chloro (Method A),—O—C(O)—C1-4alkyl (Method B) of 1-imidazole (Method C); which compoundof formula (A1) is then reacted with a source of ammonia, to yield thecorresponding compound of formula (IX).

Method A: The compound of formula (V) is reacted with a suitablyselected source of chlorine such as SOCl₂, oxalyl chloride, and thelike, preferably SOCl₂; wherein the source of chlorine is preferablypresent in an amount in the range of from about 1.0 to about 1.5 molarequivalents; in an organic solvent such as DCE, DCM, acetonitrile, andthe like, preferably DCM; preferably at a temperature in the range offrom about 10° C. to about 40° C.; to yield the corresponding compoundof formula (VI).

The compound of formula (VI) is reacted with a source of ammonia such asNH₃, NH₄OH, NH₄OAc, NH₄Cl, and the like, preferably NH₃; wherein thesource of ammonia is preferably present in an amount in the range ofform about 5 to about 10 molar equivalents; in an organic solvent suchas toluene, DCM, THF, MTBE, and the like, preferably THF; preferably ata temperature in the range of from about 0° C. to about 50° C.; to yieldthe corresponding compound of formula (IX).

Method B: The compound of formula (V) is reacted with an alkylchloroformate, such as n-butyl chloroformate, isobutyl chloroformate,ethylchloroformate, and the like, preferably isobutyl chloroformate;wherein the alkylchloroformate is preferably present in an amount in therange of from about 2.0 to about 5.0 molar equivalents; in an organicsolvent such as MTBE, toluene, THF, DCM, and the like, preferably THF;preferably at a temperature in the range of from about −10° C. to about50° C.; to yield the corresponding compound of formula (VII), wherein A²is the corresponding alkyl. For example, wherein the compound of formula(V) is reacted with isobutyl chloroformate, the product is thecorresponding compound of formula (VII), wherein A¹ is isobutyl.

The compound of formula (VII) is reacted with a source of ammonia suchas NH₃, NH₄OH, NH₄OAc, NH₄Cl, and the like, preferably NH₄Cl; whereinthe source of ammonia is preferably present in an amount of from about3.0 to about 10.0 molar equivalents; in an organic solvent such asacetone, acetonitrile, THF, and the like, preferably acetone; preferablyat a temperature in the range of from about 0° C. to about 50° C.; toyield the corresponding compound of formula (IX).

Method C: The compound of formula (V) is reacted with CDI, a knowncompound; wherein the CDI is preferably present in an amount in therange of from about 1.0 to about 1.5 molar equivalent; in an organicsolvent such as DMF, DMAc, NMP, and the like, preferably DMF; preferablyat a temperature in the range of from about 0° C. to about 50° C.; toyield the corresponding compound of formula (VIII).

The compound of formula (VIII) is reacted with a source of ammonia suchas NH₃, NH₄OH, NH₄OAc, NH₄Cl, and the like, preferably NH₄Cl; whereinthe source of ammonia is preferably present in an amount in the range offrom about 2.0 to about 6.0 molar equivalents; in an organic solventsuch as DMF, acetonitrile, NMP, and the like; preferably at atemperature in the range of from about 0° C. to about 50° C.; to yieldthe corresponding compound of formula (IX).

The present invention is further directed to processes for thepreparation of compounds of formula (XV) as outlined in Scheme 3, below.

Accordingly, a suitably substituted compound of formula (X), a knowncompound or compound prepared by known methods, wherein PG¹ is asuitably selected oxygen protecting group such as C₁₋₄alkyl, and thelike, preferably PG¹ is methyl, ethyl or t-butyl, more preferably, PG¹is ethyl, is reacted with a suitably selected source of nitrogen such asLiHMDS, NaHMDS, and the like, preferably LiHMDS; wherein the source ofnitrogen is preferably present in an amount in the range of from about3.0 to about 6.0 molar equivalents, preferably about 3.0 molarequivalents;

in the presence of CO₂ gas; wherein the CO₂ gas is preferably bubbledinto the reaction mixture in an excess amount; in an organic solventsuch as THF, MTBE, DME, glyme, and the like; preferably THF; preferablyat a temperature in the range of from about −10° C. to about 20° C.,more preferably at a temperature in the range of from about 0° C. toabout 20° C.; to yield the corresponding compound of formula (XV).

One skilled in the art will recognize that in the process as describedabove, the compound of formula (XV) is prepared in a mixture with thecorresponding acid (a compound of formula (XI)). Preferably, thecompound of formula (XV) is isolated and/or further purified accordingto known methods, for example, the compound of formula (XV) may befurther purified by acid/base workup.

Alternatively, a suitably substituted compound of formula (X), a knowncompound or compound prepared by known methods is reacted with carbondioxide; wherein the carbon dioxide is preferably bubbled into thereaction mixture in an excess amount, for example in an amount in therange of from about 10 to about 20 molar equivalents;

in the presence of a base such as n-butyl lithium, hexyl-lithium, andthe like, preferably n-butyl lithium, wherein the base is preferablypresent in an amount in the range of from about 2.0 to bout 6.0 molarequivalents, more preferably about 3.0 molar equivalents; in an organicsolvent or mixture thereof such as THF, THF/toluene, MTBE, and the like,preferably THF; preferably at a temperature in the range of from about−78° C. to about −40° C.; to yield the corresponding compound of formula(XI).

The compound of formula (XI) is reacted according to any of Methods Athrough C as outlined in more detail below, to yield the correspondingcompound of formula (XV). More particularly, as shown briefly below

the compound of formula (XI) is activated to yield the correspondingcompound of formula (A2), wherein Y¹ is chloro (Method A),—O—C(O)—C₁₋₄alkyl (Method B) of 1-imidazole (Method C); which compoundof formula (A2) is then reacted with a source of ammonia, to yield thecorresponding compound of formula (XV).

Method A: The compound of formula (XI) is reacted with a suitablyselected source of chlorine such as SOCl₂, oxalyl chloride, and thelike, preferably SOCl₂; wherein the source of chlorine is preferablypresent in an amount in the range of from about 1.0 to about 1.5 molarequivalents; in an organic solvent such as DCE, DCM, acetonitrile, andthe like, preferably DCM; preferably at a temperature in the range offrom about 10° C. to about 40° C.; to yield the corresponding compoundof formula (XII).

The compound of formula (XII) is reacted with a source of ammonia suchas NH₃, NH₄OH, NH₄OAc, NH₄Cl, and the like, preferably NH₃; wherein thesource of ammonia is preferably present in an amount in the range ofform about 5 to about 10 molar equivalents; in an organic solvent suchas toluene, DCM, THF, MTBE, and the like, preferably THF; preferably ata temperature in the range of from about 0° C. to about 50° C.; to yieldthe corresponding compound of formula (XV).

Method B: The compound of formula (XI) is reacted with an alkylchloroformate, such as n-butyl chloroformate, isobutyl chloroformate,ethylchloroformate, and the like, preferably isobutyl chloroformate;wherein the alkylchloroformate is preferably present in an amount in therange of from about 2.0 to about 5.0 molar equivalents; in an organicsolvent such as MTBE, toluene, THF, DCM, and the like, preferably THF;preferably at a temperature in the range of from about −10° C. to about50° C.; to yield the corresponding compound of formula (XIII), whereinA¹ is the corresponding alkyl. For example, wherein the compound offormula (XI) is reacted with isobutyl chloroformate, the product is thecorresponding compound of formula (XIII), wherein A¹ is isobutyl.

The compound of formula (XIII) is reacted with a source of ammonia suchas NH₃, NH₄OH, NH₄OAc, NH₄Cl, and the like, preferably NH₄Cl; whereinthe source of ammonia is preferably present in an amount of from about3.0 to about 10.0 molar equivalents; in an organic solvent such asacetone, acetonitrile, THF, and the like, preferably acetone; preferablyat a temperature in the range of from about 0° C. to about 50° C.; toyield the corresponding compound of formula (XV).

Method C: The compound of formula (XI) is reacted with CDI, a knowncompound; wherein the CDI is preferably present in an amount in therange of from about 1.0 to about 1.5 molar equivalent; in an organicsolvent such as DMF, DMAc, NMP, and the like, preferably DMF; preferablyat a temperature in the range of from about 0° C. to about 50° C.; toyield the corresponding compound of formula (XIV).

The compound of formula (XIV) is reacted with a source of ammonia suchas NH₃, NH₄OH, NH₄OAc, NH₄Cl, and the like, preferably NH₄Cl; whereinthe source of ammonia is preferably present in an amount in the range offrom about 2.0 to about 6.0 molar equivalents; in an organic solventsuch as DMF, acetonitrile, NMP, and the like; preferably at atemperature in the range of from about 0° C. to about 50° C.; to yieldthe corresponding compound of formula (XV).

In an embodiment, the present invention is directed to processes for thepreparation of a compound of formula (IX-S), as outlined in Scheme 4below.

Accordingly, a suitably substituted compound of formula (IV-S), a knowncompound or compound prepared by known methods, wherein PG¹ is asuitably selected oxygen protecting group such as C₁₋₄alkyl, and thelike, preferably PG¹ is methyl, ethyl or t-butyl, more preferably, PG¹is ethyl, is reacted with a suitably selected source of nitrogen such asLiHMDS, NaHMDS, and the like, preferably LiHMDS; wherein the source ofnitrogen is preferably present in an amount in the range of from about3.0 to about 6.0 molar equivalents, preferably about 3.0 molarequivalents;

in the presence of CO₂ gas; wherein the CO₂ gas is preferably bubbledinto the reaction mixture in an excess amount; in an organic solventsuch as THF, MTBE, DME, glyme, and the like; preferably THF; preferablyat a temperature in the range of from about −10° C. to about 20° C.,more preferably at a temperature in the range of from about 0° C. toabout 20° C.; to yield the corresponding compound of formula (IX-S).

One skilled in the art will recognize that in the process as describedabove, the compound of formula (IX-S) is prepared in a mixture with thecorresponding acid (a compound of formula (V-S)). Preferably, thecompound of formula (IX-S) is isolated and/or further purified accordingto known methods, for example, the compound of formula (IX-S) may befurther purified by acid/base workup.

Alternatively, a suitably substituted compound of formula (IV-S), aknown compound or compound prepared by known methods is reacted withcarbon dioxide; wherein the carbon dioxide is preferably bubbled intothe reaction mixture in an excess amount, for example in an amount inthe range of from about 10 to about 20 molar equivalents;

in the presence of a base such as n-butyl lithium, hexyl-lithium, andthe like, preferably n-butyl lithium, wherein the base is preferablypresent in an amount in the range of from about 2.0 to bout 6.0 molarequivalents, more preferably about 3.0 molar equivalents; in an organicsolvent or mixture thereof such as THF, THF/toluene, MTBE, and the like,preferably THF; preferably at a temperature in the range of from about−78° C. to about −40° C.; to yield the corresponding compound of formula(V-S).

The compound of formula (V-S) is reacted according to any of Methods Athrough C as outlined in more detail below, to yield the correspondingcompound of formula (IX-S). More particularly, as shown briefly below

the compound of formula (V-S) is activated to yield the correspondingcompound of formula (A3), wherein Y¹ is chloro (Method A),—O—C(O)—C₁₋₄alkyl (Method B) of 1-imidazole (Method C); which compoundof formula (A3) is then reacted with a source of ammonia, to yield thecorresponding compound of formula (IX-S).

Method A: The compound of formula (V-S) is reacted with a suitablyselected source of chlorine such as SOCl₂, oxalyl chloride, and thelike, preferably SOCl₂; wherein the source of chlorine is preferablypresent in an amount in the range of from about 1.0 to about 1.5 molarequivalents; in an organic solvent such as DCE, DCM, acetonitrile, andthe like, preferably DCM; preferably at a temperature in the range offrom about 10° C. to about 40° C.; to yield the corresponding compoundof formula (VI-S).

The compound of formula (VI-S) is reacted with a source of ammonia suchas NH₃, NH₄OH, NH₄OAc, NH₄Cl, and the like, preferably NH₃; wherein thesource of ammonia is preferably present in an amount in the range ofform about 5 to about 10 molar equivalents; in an organic solvent suchas toluene, DCM, THF, MTBE, and the like, preferably THF; preferably ata temperature in the range of from about 0° C. to about 50° C.; to yieldthe corresponding compound of formula (IX-S).

Method B: The compound of formula (V-S) is reacted with an alkylchloroformate, such as n-butyl chloroformate, isobutyl chloroformate,ethylchloroformate, and the like, preferably isobutyl chloroformate;wherein the alkylchloroformate is preferably present in an amount in therange of from about 2.0 to about 5.0 molar equivalents; in an organicsolvent such as MTBE, toluene, THF, DCM, and the like, preferably THF;preferably at a temperature in the range of from about −10° C. to about50° C.; to yield the corresponding compound of formula (VII-S), whereinA¹ is the corresponding alkyl. For example, wherein the compound offormula (V-S) is reacted with isobutyl chloroformate, the product is thecorresponding compound of formula (VII-S), wherein A¹ is isobutyl.

The compound of formula (VII-S) is reacted with a source of ammonia suchas NH₃, NH₄OH, NH₄OAc, NH₄Cl, and the like, preferably NH₄Cl; whereinthe source of ammonia is preferably present in an amount of from about3.0 to about 10.0 molar equivalents; in an organic solvent such asacetone, acetonitrile, THF, and the like, preferably acetone; preferablyat a temperature in the range of from about 0° C. to about 50° C.; toyield the corresponding compound of formula (IX-S).

Method C: The compound of formula (V-S) is reacted with CDI, a knowncompound; wherein the CDI is preferably present in an amount in therange of from about 1.0 to about 1.5 molar equivalent; in an organicsolvent such as DMF, DMAc, NMP, and the like, preferably DMF; preferablyat a temperature in the range of from about 0° C. to about 50° C.; toyield the corresponding compound of formula (VIII-S).

The compound of formula (VIII-S) is reacted with a source of ammoniasuch as NH₃, NH₄OH, NH₄OAc, NH₄Cl, and the like, preferably NH₄Cl;wherein the source of ammonia is preferably present in an amount in therange of from about 2.0 to about 6.0 molar equivalents; in an organicsolvent such as DMF, acetonitrile, NMP, and the like; preferably at atemperature in the range of from about 0° C. to about 50° C.; to yieldthe corresponding compound of formula (IX-S).

In another embodiment, the present invention is directed to processesfor the preparation of a compound of formula (XV-S), as outlined inScheme 5 below.

Accordingly, a suitably substituted compound of formula (X-S), a knowncompound or compound prepared by known methods, wherein PG¹ is asuitably selected oxygen protecting group such as C₁₋₄alkyl, and thelike, preferably PG¹ is methyl, ethyl or t-butyl, more preferably, PG¹is ethyl, and wherein PG² is a suitably selected oxygen protecting groupsuch as C₁₋₄alkyl, and the like, preferably PG² is methyl, ethyl ort-butyl, more preferably, PG² is ethyl, wherein PG¹ and PG² arepreferably the same; is reacted with a suitably selected source ofnitrogen such as LiHMDS, NaHMDS, and the like, preferably LiHMDS;wherein the source of nitrogen is preferably present in an amount in therange of from about 3.0 to about 6.0 molar equivalents, preferably about3.0 molar equivalents;

in the presence of CO₂ gas; wherein the CO₂ gas is preferably bubbledinto the reaction mixture in an excess amount; in an organic solventsuch as THF, MTBE, DME, glyme, and the like; preferably THF; preferablyat a temperature in the range of from about −10° C. to about 20° C.,more preferably at a temperature in the range of from about 0° C. toabout 20° C.; to yield the corresponding compound of formula (XV-S).

One skilled in the art will recognize that in the process as describedabove, the compound of formula (XV-S) is prepared in a mixture with thecorresponding acid (a compound of formula (XI-S)). Preferably, thecompound of formula (XV-S) is isolated and/or further purified accordingto known methods, for example, the compound of formula (XV-S) may befurther purified by acid/base workup.

Alternatively, a suitably substituted compound of formula (X-S), a knowncompound or compound prepared by known methods is reacted with carbondioxide; wherein the carbon dioxide is preferably bubbled into thereaction mixture in an excess amount, for example in an amount in therange of from about 10 to about 20 molar equivalents;

in the presence of a base such as n-butyl lithium, hexyl-lithium, andthe like, preferably n-butyl lithium, wherein the base is preferablypresent in an amount in the range of from about 2.0 to bout 6.0 molarequivalents, more preferably about 3.0 molar equivalents; in an organicsolvent or mixture thereof such as THF, THF/toluene, MTBE, and the like,preferably THF; preferably at a temperature in the range of from about−78° C. to about −40° C.; to yield the corresponding compound of formula(XI-S).

The compound of formula (XI-S) is reacted according to any of Methods Athrough C as outlined in more detail below, to yield the correspondingcompound of formula (XV-S). More particularly, as shown briefly below

the compound of formula (XI-S) is activated to yield the correspondingcompound of formula (A4), wherein Y¹ is chloro (Method A),—O—C(O)—C₁₋₄alkyl (Method B) of 1-imidazole (Method C); which compoundof formula (A4) is then reacted with a source of ammonia, to yield thecorresponding compound of formula (XV-S).

Method A: The compound of formula (XI-S) is reacted with a suitablyselected source of chlorine such as SOCl₂, oxalyl chloride, and thelike, preferably SOCl₂; wherein the source of chlorine is preferablypresent in an amount in the range of from about 1.0 to about 1.5 molarequivalents; in an organic solvent such as DCE, DCM, acetonitrile, andthe like, preferably DCM; preferably at a temperature in the range offrom about 10° C. to about 40° C.; to yield the corresponding compoundof formula (XII-S).

The compound of formula (XII-S) is reacted with a source of ammonia suchas NH₃, NH₄OH, NH₄OAc, NH₄Cl, and the like, preferably NH₃; wherein thesource of ammonia is preferably present in an amount in the range ofform about 5 to about 10 molar equivalents; in an organic solvent suchas toluene, DCM, THF, MTBE, and the like, preferably THF; preferably ata temperature in the range of from about 0° C. to about 50° C.; to yieldthe corresponding compound of formula (XV-S).

Method B: The compound of formula (XI-S) is reacted with an alkylchloroformate, such as n-butyl chloroformate, isobutyl chloroformate,ethylchloroformate, and the like, preferably isobutyl chloroformate;wherein the alkylchloroformate is preferably present in an amount in therange of from about 2.0 to about 5.0 molar equivalents; in an organicsolvent such as MTBE, toluene, THF, DCM, and the like, preferably THF;preferably at a temperature in the range of from about −10° C. to about50° C.; to yield the corresponding compound of formula (XIII-S), whereinA¹ is the corresponding alkyl. For example, wherein the compound offormula (XI-S) is reacted with isobutyl chloroformate, the product isthe corresponding compound of formula (XIII-S), wherein A¹ is isobutyl.

The compound of formula (XIII-S) is reacted with a source of ammoniasuch as NH₃, NH₄OH, NH₄OAc, NH₄Cl, and the like, preferably NH₄Cl;wherein the source of ammonia is preferably present in an amount of fromabout 3.0 to about 10.0 molar equivalents; in an organic solvent such asacetone, acetonitrile, THF, and the like, preferably acetone; preferablyat a temperature in the range of from about 0° C. to about 50° C.; toyield the corresponding compound of formula (XV-S).

Method C: The compound of formula (XI-S) is reacted with CDI, a knowncompound; wherein the CDI is preferably present in an amount in therange of from about 1.0 to about 1.5 molar equivalent; in an organicsolvent such as DMF, DMAc, NMP, and the like, preferably DMF; preferablyat a temperature in the range of from about 0° C. to about 50° C.; toyield the corresponding compound of formula (XIV-S).

The compound of formula (XIV-S) is reacted with a source of ammonia suchas NH₃, NH₄OH, NH₄OAc, NH₄Cl, and the like, preferably NH₄Cl; whereinthe source of ammonia is preferably present in an amount in the range offrom about 2.0 to about 6.0 molar equivalents; in an organic solventsuch as DMF, acetonitrile, NMP, and the like; preferably at atemperature in the range of from about 0° C. to about 50° C.; to yieldthe corresponding compound of formula (XV-S).

The present invention is directed to a process for the preparation ofcompounds of formula (I), preferably compounds of formula (I) wherein R⁶is other than hydroxy, as described in more detail in Scheme 6 below.

Accordingly, a suitably substituted compound of formula (IV), whereinPG¹ is a suitably substituted oxygen protecting group such as C₁₋₄alkyl,phenyl, benzyl, and the like, preferably, PG¹ is methyl, ethyl ort-butyl, more preferably, PG¹ is ethyl; is reacted according to any ofthe methods as described in Scheme 2 above; to yield the correspondingcompound of formula (IX).

The compound of formula (IX) is reacted with a suitably substitutedcompound of formula (XVI); wherein the compound of formula (XVI) ispreferably present in an excess of the corresponding trans orientation,more preferably, the compound of formula (XVI) is present in thecorresponding trans orientation; wherein the compound of formula (XVI)is preferably present in an amount in the range of from about 1.0 toabout 2.0 molar equivalents (relative to the moles of the compound offormula (IX)), more preferably in an amount in the range of from about1.0 to about 1.5 molar equivalents, more preferably still in an amountof about 1.1 to about 1.2 molar equivalents; in the presence of CuI, andthe like, wherein the CuI is preferably present in an amount in therange of from about 0.1 to about 1.0 molar equivalents, more preferably,in an amount in the range of from about 0.1 to about 0.5 molarequivalents, more preferably in an amount of about 0.2 molarequivalents;

in the presence of an inorganic base, such as Cs₂CO₃, K₂CO₃, K₃PO₄, andthe like, preferably Cs₂CO₃; wherein the inorganic base is preferablypresent in an amount in the range of from about 0.5 to about 2.0 molarequivalents, more preferably, in an amount in the range of from about0.5 to about 3.0 molar equivalents, more preferably, in an amount ofabout 1.0 molar equivalents;

in the presence of a suitably selected ligand such asN,N-dimethylethylenediamine, N,N-dimethylglycine, dicyclohexyldiamine,and the like, preferably, N,N-dimethylethylenediamine; wherein theligand is preferably present in an amount in the range of from about 0.2to about 2.0 molar equivalents, more preferably, in an amount in therange of from about 0.2 to about 1.0 molar equivalents, more preferably,in an amount of about 0.4 molar equivalents;

in an organic solvent or mixtures thereof, such as DMA,N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and thelike, preferably DMA; preferably, at a temperature in the range of fromabout 50° C. to about 100° C., preferably at about 75° C.; to yield thecorresponding compound of formula (XVII).

Preferably, the compound of formula (IX) is reacted with the compound offormula (XVI) under an inert atmosphere, for example under nitrogen orargon. Preferably, a mixture of the compound of formula (IX), the CuI,the ligand, the inorganic base and the organic solvent is heated to atemperature in the range of from about 50° C. to about 100, to yield ahomogeneous mixture; prior to addition of the compound of formula (XVI).

Preferably, in the reaction of the compound of formula (IX) with thecompound of formula (XVI), the compound of formula (XVI) is present inan excess of its geometrical isomer, more particularly, itscorresponding trans isomer, to yield the compound of formula (XVII) inits corresponding trans isomer.

When the compound of formula (IX) is reacted with a compound of formula(XVI), wherein the compound of formula (XVI) is present in either itscorresponding cis configuration or as a mixture of its corresponding cisand trans configurations, then the reaction proceeds to yield thecompound of formula (XVII) as a mixture of its corresponding cis andtrans configurations.

The compound of formula (XVII) is de-protected according to knownmethods, to yield the corresponding compound of formula (Ia). Forexample, the compound of formula (XVII) may be reacted with a suitablyselected de-alkylating agent such as TMS-Br, TMS-I, Br₃, and the like;wherein the de-alkylating agent is preferably present in an amount ofabout 2.0 molar equivalents; in the presence of a proton scavenger suchas pyridine, N-methylmorpholine, proton sponge (i.e.N,N,N′,N′-tetramethyl-1,8-diaminonaphthalene), and the like, preferablypyridine;

in an organic solvent such as acetonitrile, DCM, DCE, and the like,preferably acetonitrile; preferably at a temperature in the range offrom about 10° C. to about 30° C., more preferably at about 10° C.; toyield the corresponding compound of formula (Ia), a compound of formula(I) wherein R⁵ is hydrogen.

Alternatively, the compound of formula (XVII) may be reacted with asuitably selected de-alkylating agent such as TMS-Cl, and the like; inthe presence of NaI, and the like; in an organic solvent such asacetonitrile, and the like; to yield the corresponding compound offormula (Ia), a compound of formula (I) wherein R⁵ is hydrogen.

The compound of formula (Ia) may be optionally further reacted with asuitably substituted compound of formula (XVIII), wherein Q¹ is asuitably selected leaving group such as Br, Cl, I, and the like,preferably Cl, a known compound or compound prepared by known methods;wherein the compound of formula (XVIII) is preferably present in anamount in the range of from about 1.0 to about 3.0 molar equivalents,more preferably about 1.7 molar equivalents; in the presence of anorganic base such as DIPEA, TEA, pyridine, and the like, preferablyDIPEA; wherein the organic base is preferably present in an amount inthe range of from about 1.5 to about 5.0 molar equivalents; morepreferably about 2.0 molar equivalents; in an organic solvent such DMFand the like; preferably at a temperature in the range of from about 50°C. to about 120° C., more preferably at about 73° C.; to yield thecorresponding compound of formula (Ib), a compound of formula (I)wherein R⁵ is other than hydrogen.

Compounds of formula (I) wherein R⁶ is hydroxy may be prepared accordingto the process outlined in Scheme 7 below.

Accordingly, a suitably substituted compound of formula (X), wherein PG¹is a suitably substituted oxygen protecting group such as C₁₋₄alkyl,phenyl, benzyl, and the like, and wherein PG² is a suitably selectedoxygen protecting group such as C₁₋₄alkyl, phenyl, benzyl, and the like,and wherein PG¹ and PG² are the same or different oxygen protectinggroups, preferably PG¹ and PG² are different oxygen protecting groups;is reacted according to any of the methods as described in Scheme 3above; to yield the corresponding compound of formula (XV).

The compound of formula (XV) is reacted with a suitably substitutedcompound of formula (XVI); wherein the compound of formula (XVI) ispreferably present in an excess of the corresponding trans orientation,more preferably, the compound of formula (XVI) is present in thecorresponding trans orientation; wherein the compound of formula (XVI)is preferably present in an amount in the range of from about 1.0 toabout 2.0 molar equivalents (relative to the moles of the compound offormula (XV)), more preferably in an amount in the range of from about1.0 to about 1.5 molar equivalents, more preferably still in an amountof about 1.1 to about 1.2 molar equivalents;

in the presence of CuI, and the like, wherein the CuI is preferablypresent in an amount in the range of from about 0.1 to about 1.0 molarequivalents, more preferably, in an amount in the range of from about0.1 to about 0.5 molar equivalents, more preferably in an amount ofabout 0.2 molar equivalents;

in the presence of an inorganic base, such as Cs₂CO₃, K₂CO₃, K₃PO₄, andthe like, preferably Cs₂CO₃; wherein the inorganic base is preferablypresent in an amount in the range of from about 0.5 to about 2.0 molarequivalents, more preferably, in an amount in the range of from about0.5 to about 3.0 molar equivalents, more preferably, in an amount ofabout 1.0 molar equivalents;

in the presence of a suitably selected ligand such asN,N-dimethylethylenediamine, N,N-dimethylglycine, dicyclohexyldiamine,and the like, preferably, N,N-dimethylethylenediamine; wherein theligand is preferably present in an amount in the range of from about 0.2to about 2.0 molar equivalents, more preferably, in an amount in therange of from about 0.2 to about 1.0 molar equivalents, more preferably,in an amount of about 0.4 molar equivalents;

in an organic solvent or mixtures thereof, such as DMA,N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and thelike, preferably DMA; at a temperature in the range of from about 50° C.to about 100° C., preferably at about 75° C.; to yield the correspondingcompound of formula (XIX).

Preferably, the compound of formula (XV) is reacted with the compound offormula (XVI) under an inert atmosphere, for example under nitrogen orargon. Preferably, a mixture of the compound of formula (XV), the CuI,the ligand, the inorganic base and the organic solvent is heated to atemperature in the range of from about 50° C. to about 100, to yield ahomogeneous mixture; prior to addition of the compound of formula (XVI).

Preferably, in the reaction of the compound of formula (XV) with thecompound of formula (XVI), the compound of formula (XVI) is present inan excess of its geometrical isomer, more particularly, itscorresponding trans isomer, to yield the compound of formula (XIX) inits corresponding trans isomer. When the compound of formula (XV) isreacted with a compound of formula (XVI), wherein the compound offormula (XVI) is present in either its corresponding cis configurationor as a mixture of its corresponding cis and trans configurations, thenthe reaction proceeds to yield the compound of formula (XIX) as amixture of its corresponding cis and trans configurations.

The compound of formula (XIX) is de-protected at both the PG¹ and PG²according to known methods, to yield the corresponding compound offormula (Ic). For example, the compound of formula (XIX) is reacted witha suitably selected de-alkylating agent such as TMS-Br, TMS-I, Br₃, andthe like; wherein the de-alkylating agent is preferably present in anamount of about 2.0 molar equivalents; in the presence of a protonscavenger such as pyridine, N-methylmorpholine, proton sponge (i.e.N,N,N′,N′-tetramethyl-1,8-diaminonaphthalene), and the like, preferablypyridine; in an organic solvent such as acetonitrile, DCM, DCE, and thelike, preferably acetonitrile; preferably at a temperature in the rangeof from about 10° C. to about 30° C., more preferably at about 10° C.;to yield the corresponding compound of formula (Ic).

Alternatively, the compound of formula (XIX) may be reacted with asuitably selected de-alkylating agent such as TMS-Cl, and the like; inthe presence of NaI, and the like; in an organic solvent such asacetonitrile, and the like; to yield the corresponding compound offormula (Ic).

The compound of formula (Ic) may be optionally further reacted with asuitably substituted compound of formula (XVIII), wherein Q¹ is asuitably selected leaving group such as Br, Cl, I, and the like,preferably Cl, a known compound or compound prepared by known methods;wherein the compound of formula (XVIII) is preferably present in anamount in the range of from about 1.0 to about 3.0 molar equivalents,more preferably about 1.7 molar equivalents; in the presence of anorganic base such as DIPEA, TEA, pyridine, and the like, preferablyDIPEA; wherein the organic base is preferably present in an amount inthe range of from about 1.5 to about 5.0 molar equivalents; morepreferably about 2.0 molar equivalents; in an organic solvent such DMFand the like; preferably at a temperature in the range of from about 50°C. to about 120° C., more preferably at about 73° C.; to yield thecorresponding compound of formula (Id).

Alternatively, the compound of formula (XIX) is de-protected at eitherPG¹ or PG², according to known methods, to yield the correspondingcompound of formula (XX), wherein PG⁰ is the un-protected PG group. Forexample, wherein the compound of formula (XIX) is de-protected to removePG¹, then in the resulting compound of formula (XX), PG⁰ is PG².Alternatively, wherein the compound of formula (XIX) is de-protected toremove PG², then in the resulting compound of formula (XX), PG⁰ is PG¹.

The compound of formula (XX) is reacted with a suitably substitutedcompound of formula (XVIII), wherein Q¹ is a suitably selected leavinggroup such as Br, Cl, I, and the like, preferably Cl, a known compoundor compound prepared by known methods; wherein the compound of formula(XVIII) is preferably present in an amount in the range of from about1.0 to about 3.0 molar equivalents, more preferably about 1.7 molarequivalents; in the presence of an organic base such as DIPEA, TEA,pyridine, and the like, preferably DIPEA; wherein the organic base ispreferably present in an amount in the range of from about 1.5 to about5.0 molar equivalents; more preferably about 2.0 molar equivalents; inan organic solvent such DMF and the like; preferably at a temperature inthe range of from about 50° C. to about 120° C., more preferably atabout 73° C.; to yield the corresponding compound of formula (XXI).

The compound of formula (XXI) is then de-protected according to knownmethods, as described herein, to yield the corresponding compound offormula (Id).

In an embodiment, the present invention is directed to a process for thepreparation of compounds of formula (X-S), as outlined in Scheme 8below.

Accordingly, a suitably substituted compound of formula (IV-S), whereinPG¹ is a suitably substituted oxygen protecting group such as C₁₋₄alkyl,phenyl, benzyl, and the like, preferably, PG¹ is methyl, ethyl ort-butyl, more preferably, PG¹ is ethyl; is reacted according to any ofthe methods as described in Schemes 2 and 4 above; to yield thecorresponding compound of formula (IX-S).

The compound of formula (IX-S) is reacted with a suitably substitutedcompound of formula (XVI-S); wherein the compound of formula (XVI-S) ispreferably present in an excess of the corresponding trans orientation,more preferably, the compound of formula (XVI-S) is present in thecorresponding trans orientation; wherein the compound of formula (XVI-S)is preferably present in an amount in the range of from about 1.0 toabout 2.0 molar equivalents (relative to the moles of the compound offormula (IX-S)), more preferably in an amount in the range of from about1.0 to about 1.5 molar equivalents, more preferably still in an amountof about 1.1 to about 1.2 molar equivalents;

in the presence of CuI, and the like, wherein the CuI is preferablypresent in an amount in the range of from about 0.1 to about 1.0 molarequivalents, more preferably, in an amount in the range of from about0.1 to about 0.5 molar equivalents, more preferably in an amount ofabout 0.2 molar equivalents;

in the presence of an inorganic base, such as Cs₂CO₃, K₂CO₃, K₃PO₄, andthe like, preferably Cs₂CO₃; wherein the inorganic base is preferablypresent in an amount in the range of from about 0.5 to about 2.0 molarequivalents, more preferably, in an amount in the range of from about0.5 to about 3.0 molar equivalents, more preferably, in an amount ofabout 1.0 molar equivalents;

in the presence of a suitably selected ligand such asN,N-dimethylethylenediamine, N,N-dimethylglycine, dicyclohexyldiamine,and the like, preferably, N,N-dimethylethylenediamine; wherein theligand is preferably present in an amount in the range of from about 0.2to about 2.0 molar equivalents, more preferably, in an amount in therange of from about 0.2 to about 1.0 molar equivalents, more preferably,in an amount of about 0.4 molar equivalents;

in an organic solvent or mixtures thereof, such as DMA,N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and thelike, preferably DMA; preferably, at a temperature in the range of fromabout 50° C. to about 100° C., preferably at about 75° C.; to yield thecorresponding compound of formula (XVII-S).

Preferably, the compound of formula (IX-S) is reacted with the compoundof formula (XVI-S) under an inert atmosphere, for example under nitrogenor argon. Preferably, a mixture of the compound of formula (IX-S), theCuI, the ligand, the inorganic base and the organic solvent is heated toa temperature in the range of from about 50° C. to about 100, to yield ahomogeneous mixture; prior to addition of the compound of formula(XVI-S).

Preferably, in the reaction of the compound of formula (IX-S) with thecompound of formula (XVI-S), the compound of formula (XVI-S) is presentin an excess of its geometrical isomer, more particularly, itscorresponding trans isomer, to yield the compound of formula (XVII-S) inits corresponding trans isomer. When the compound of formula (IX-S) isreacted with a compound of formula (XVI-S), wherein the compound offormula (XVI-S) is present in either its corresponding cis configurationor as a mixture of its corresponding cis and trans configurations, thenthe reaction proceeds to yield the compound of formula (XVII-S) as amixture of its corresponding cis and trans configurations.

The compound of formula (XVII-S) is de-protected according to knownmethods, to yield the corresponding compound of formula (Ie). Forexample, the compound of formula (XVII-S) may be reacted with a suitablyselected de-alkylating agent such as TMS-Br, TMS-I, Br₃, and the like;wherein the de-alkylating agent is preferably present in an amount ofabout 2.0 molar equivalents; in the presence of a proton scavenger suchas pyridine, N-methylmorpholine, proton sponge (i.e.N,N,N′,N′-tetramethyl-1,8-diaminonaphthalene), and the like, preferablypyridine;

in an organic solvent such as acetonitrile, DCM, DCE, and the like,preferably acetonitrile; preferably at a temperature in the range offrom about 10° C. to about 30° C., more preferably at about 10° C.; toyield the corresponding compound of formula (I-Sa), a compound offormula (X-S) wherein R⁵ is hydrogen.

Alternatively, the compound of formula (XVII-S) may be reacted with asuitably selected de-alkylating agent such as TMS-Cl, and the like; inthe presence of NaI, and the like; in an organic solvent such asacetonitrile, and the like; to yield the corresponding compound offormula (I-Sa), a compound of formula (X-S) wherein R⁵ is hydrogen.

The compound of formula (I-Sa) may be optionally further reacted with asuitably substituted compound of formula (XVIII), wherein Q¹ is asuitably selected leaving group such as Br, Cl, I, and the like,preferably Cl, a known compound or compound prepared by known methods;wherein the compound of formula (XVIII) is preferably present in anamount in the range of from about 1.0 to about 3.0 molar equivalents,more preferably about 1.7 molar equivalents; in the presence of anorganic base such as DIPEA, TEA, pyridine, and the like, preferablyDIPEA; wherein the organic base is preferably present in an amount inthe range of from about 1.5 to about 5.0 molar equivalents; morepreferably about 2.0 molar equivalents; in an organic solvent such DMFand the like; preferably at a temperature in the range of from about 50°C. to about 120° C., more preferably at about 73° C.; to yield thecorresponding compound of formula (I-Sb), a compound of formula (X-S)wherein R⁵ is other than hydrogen.

In additional embodiments, the present invention is further directed toprocesses for the preparation of compounds of formula (X-S) wherein R⁶is hydroxy as outlined in Scheme 9 below.

Accordingly, a suitably substituted compound of formula (X-S), whereinPG¹ is a suitably substituted oxygen protecting group such as C₁₋₄alkyl,phenyl, benzyl, and the like, and wherein PG² is a suitably selectedoxygen protecting group such as C₁₋₄alkyl, phenyl, benzyl, and the like,and wherein PG¹ and PG² are the same or different oxygen protectinggroups, preferably PG¹ and PG² are different oxygen protecting groups;is reacted according to any of the methods as described in Scheme 3 and5 above; to yield the corresponding compound of formula (XV-S).

The compound of formula (XV-S) is reacted with a suitably substitutedcompound of formula (XVI-S); wherein the compound of formula (XVI-S) ispreferably present in an excess of the corresponding trans orientation,more preferably, the compound of formula (XVI-S) is present in thecorresponding trans orientation; wherein the compound of formula (XVI-S)is preferably present in an amount in the range of from about 1.0 toabout 2.0 molar equivalents (relative to the moles of the compound offormula (XV-S)), more preferably in an amount in the range of from about1.0 to about 1.5 molar equivalents, more preferably still in an amountof about 1.1 to about 1.2 molar equivalents;

in the presence of CuI, and the like, wherein the CuI is preferablypresent in an amount in the range of from about 0.1 to about 1.0 molarequivalents, more preferably, in an amount in the range of from about0.1 to about 0.5 molar equivalents, more preferably in an amount ofabout 0.2 molar equivalents;

in the presence of an inorganic base, such as Cs₂CO₃, K₂CO₃, K₃PO₄, andthe like, preferably Cs₂CO₃; wherein the inorganic base is preferablypresent in an amount in the range of from about 0.5 to about 2.0 molarequivalents, more preferably, in an amount in the range of from about0.5 to about 3.0 molar equivalents, more preferably, in an amount ofabout 1.0 molar equivalents;

in the presence of a suitably selected ligand such asN,N-dimethylethylenediamine, N,N-dimethylglycine, dicyclohexyldiamine,and the like, preferably, N,N-dimethylethylenediamine; wherein theligand is preferably present in an amount in the range of from about 0.2to about 2.0 molar equivalents, more preferably, in an amount in therange of from about 0.2 to about 1.0 molar equivalents, more preferably,in an amount of about 0.4 molar equivalents;

in an organic solvent or mixtures thereof, such as DMA,N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and thelike, preferably DMA; at a temperature in the range of from about 50° C.to about 100° C., preferably at about 75° C.; to yield the correspondingcompound of formula (XIX-S).

Preferably, the compound of formula (XV-S) is reacted with the compoundof formula (XVI-S) under an inert atmosphere, for example under nitrogenor argon. Preferably, a mixture of the compound of formula (XV-S), theCuI, the ligand, the inorganic base and the organic solvent is heated toa temperature in the range of from about 50° C. to about 100, to yield ahomogeneous mixture; prior to addition of the compound of formula(XVI-S).

Preferably, in the reaction of the compound of formula (XV-S) with thecompound of formula (XVI-S), the compound of formula (XVI-S) is presentin an excess of its geometrical isomer, more particularly, itscorresponding trans isomer, to yield the compound of formula (XIX-S) inits corresponding trans isomer. When the compound of formula (XV-S) isreacted with a compound of formula (XVI-S), wherein the compound offormula (XVI-S) is present in either its corresponding cis configurationor as a mixture of its corresponding cis and trans configurations, thenthe reaction proceeds to yield the compound of formula (XIX) as amixture of its corresponding cis and trans configurations.

The compound of formula (XIX-S) is de-protected at both the PG¹ and PG²according to known methods, to yield the corresponding compound offormula (I-Sc). For example, the compound of formula (XIX-S) is reactedwith a suitably selected de-alkylating agent such as TMS-Br, TMS-I, Br₃,and the like; wherein the de-alkylating agent is preferably present inan amount of about 2.0 molar equivalents; in the presence of a protonscavenger such as pyridine, N-methylmorpholine, proton sponge (i.e.N,N,N′,N′-tetramethyl-1,8-diaminonaphthalene), and the like, preferablypyridine; in an organic solvent such as acetonitrile, DCM, DCE, and thelike, preferably acetonitrile; preferably at a temperature in the rangeof from about 10° C. to about 30° C., more preferably at about 10° C.;to yield the corresponding compound of formula (I-Sc).

Alternatively, the compound of formula (XIX-S) may be reacted with asuitably selected de-alkylating agent such as TMS-Cl, and the like; inthe presence of NaI, and the like; in an organic solvent such asacetonitrile, and the like; to yield the corresponding compound offormula (I-Sc).

The compound of formula (I-Sc) may be optionally further reacted with asuitably substituted compound of formula (XVIII), wherein Q¹ is asuitably selected leaving group such as Br, Cl, I, and the like,preferably Cl, a known compound or compound prepared by known methods;wherein the compound of formula (XVIII) is preferably present in anamount in the range of from about 1.0 to about 3.0 molar equivalents,more preferably about 1.7 molar equivalents; in the presence of anorganic base such as DIPEA, TEA, pyridine, and the like, preferablyDIPEA; wherein the organic base is preferably present in an amount inthe range of from about 1.5 to about 5.0 molar equivalents; morepreferably about 2.0 molar equivalents; in an organic solvent such DMFand the like; preferably at a temperature in the range of from about 50°C. to about 120° C., more preferably at about 73° C.; to yield thecorresponding compound of formula (I-Sd).

Alternatively, the compound of formula (XIX-S) is de-protected at eitherPG¹ or PG², according to known methods, to yield the correspondingcompound of formula (X-S), wherein PG⁰ is the un-protected PG group. Forexample, wherein the compound of formula (XIX-S) is de-protected toremove PG¹, then in the resulting compound of formula (X-S), PG⁰ is PG².Alternatively, wherein the compound of formula (XIX-S) is de-protectedto remove PG², then in the resulting compound of formula (X-S), PG⁰ isPG¹.

The compound of formula (X-S) is reacted with a suitably substitutedcompound of formula (XVIII), wherein Q¹ is a suitably selected leavinggroup such as Br, Cl, I, and the like, preferably Cl, a known compoundor compound prepared by known methods; wherein the compound of formula(XVIII) is preferably present in an amount in the range of from about1.0 to about 3.0 molar equivalents, more preferably about 1.7 molarequivalents; in the presence of an organic base such as DIPEA, TEA,pyridine, and the like, preferably DIPEA; wherein the organic base ispreferably present in an amount in the range of from about 1.5 to about5.0 molar equivalents; more preferably about 2.0 molar equivalents; inan organic solvent such DMF and the like; preferably at a temperature inthe range of from about 50° C. to about 120° C., more preferably atabout 73° C.; to yield the corresponding compound of formula (XXI-S).

The compound of formula (XXI-S) is then de-protected according to knownmethods, as described herein, to yield the corresponding compound offormula (I-Sd).

The present invention is further directed to a process for thepreparation of a compound of formula (I-A), as outlined in Scheme 10below.

Accordingly, a suitably substituted compound of formula (IV-S), whereinPG¹ is a suitably substituted oxygen protecting group such as C₁₋₄alkyl,phenyl, benzyl, and the like, preferably, PG¹ is methyl, ethyl ort-butyl, more preferably, PG¹ is ethyl; is reacted according to any ofthe methods as described in Schemes 2 and 4 above; to yield thecorresponding compound of formula (IX-S).

The compound of formula (IX-S) is reacted with a suitably substitutedcompound of formula (XVI-S); wherein the compound of formula (XVI-A) ispreferably present in an excess of the corresponding trans orientation,more preferably, the compound of formula (XVI-A) is present in thecorresponding trans orientation; wherein the compound of formula (XVI-A)is preferably present in an amount in the range of from about 1.0 toabout 2.0 molar equivalents (relative to the moles of the compound offormula (IV-S)), more preferably in an amount in the range of from about1.0 to about 1.5 molar equivalents, more preferably still in an amountof about 1.1 to about 1.2 molar equivalents;

in the presence of CuI, and the like, wherein the CuI is preferablypresent in an amount in the range of from about 0.1 to about 1.0 molarequivalents, more preferably, in an amount in the range of from about0.1 to about 0.5 molar equivalents, more preferably in an amount ofabout 0.2 molar equivalents;

in the presence of an inorganic base, such as Cs₂CO₃, K₂CO₃, K₃PO₄, andthe like, preferably Cs₂CO₃; wherein the inorganic base is preferablypresent in an amount in the range of from about 0.5 to about 2.0 molarequivalents, more preferably, in an amount in the range of from about0.5 to about 3.0 molar equivalents, more preferably, in an amount ofabout 1.0 molar equivalents; in the presence of a suitably selectedligand such as N,N-dimethylethylenediamine, N,N-dimethylglycine,dicyclohexyldiamine, and the like, preferably,N,N-dimethylethylenediamine; wherein the ligand is preferably present inan amount in the range of from about 0.2 to about 2.0 molar equivalents,more preferably, in an amount in the range of from about 0.2 to about1.0 molar equivalents, more preferably, in an amount of about 0.4 molarequivalents;

in an organic solvent or mixtures thereof, such as DMA,N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and thelike, preferably DMA; preferably at a temperature in the range of fromabout 50° C. to about 100° C., preferably at about 75° C.; to yield thecorresponding compound of formula (IX-S).

Preferably, the compound of formula (IX-S) is reacted with the compoundof formula (XVI-A) under an inert atmosphere, for example under nitrogenor argon. Preferably, a mixture of the compound of formula (IX-S), theCuI, the ligand, the inorganic base and the organic solvent is heated toa temperature in the range of from about 50° C. to about 100, to yield ahomogeneous mixture; prior to addition of the compound of formula(XVI-A).

Preferably, in the reaction of the compound of formula (IX-S) with thecompound of formula (XVI-A), the compound of formula (XVI-A) is presentin an excess of its geometrical isomer, more particularly, itscorresponding trans isomer, to yield the compound of formula (XVII-A) inits corresponding trans isomer. When the compound of formula (IX-S) isreacted with a compound of formula (XVI-A), wherein the compound offormula (XVI-A) is present in either its corresponding cis configurationor as a mixture of its corresponding cis and trans configurations, thenthe reaction proceeds to yield the compound of formula (XVII-A) as amixture of its corresponding cis and trans configurations.

The compound of formula (XVII-A) is de-protected according to knownmethods, to yield the corresponding compound of formula (I-A). Forexample, the compound of formula (XVII-A) may be reacted with a suitablyselected de-alkylating agent such as TMS-Br, TMS-I, Br₃, and the like;wherein the de-alkylating agent is preferably present in an amount ofabout 2.0 molar equivalents; in the presence of a proton scavenger suchas pyridine, N-methylmorpholine, proton sponge (i.e.N,N,N′,N′-tetramethyl-1,8-diaminonaphthalene), and the like, preferablypyridine; in an organic solvent such as acetonitrile, DCM, DCE, and thelike, preferably acetonitrile; preferably at a temperature in the rangeof from about 10° C. to about 30° C., more preferably at about 10° C.;to yield the corresponding compound of formula (I-A).

Alternatively, the compound of formula (XVII-A) may be reacted with asuitably selected de-alkylating agent such as TMS-Cl, and the like; inthe presence of NaI, and the like; in an organic solvent such asacetonitrile, and the like; to yield the corresponding compound offormula (I-A).

The present invention is further directed to a process for thepreparation of a compound of formula (I-B), as outlined in Scheme 11below.

Accordingly, a suitably substituted compound of formula (X-S), whereinPG¹ is a suitably substituted oxygen protecting group such as C₁₋₄alkyl,phenyl, benzyl, and the like, preferably, PG¹ is methyl, ethyl ort-butyl, more preferably, PG¹ is ethyl; is reacted according to any ofthe methods as described in Schemes 3 and 5 above; to yield thecorresponding compound of formula (XV-S).

The compound of formula (XV-S) is reacted with a suitably substitutedcompound of formula (XVI-A); wherein the compound of formula (XVI-A) ispreferably present in an excess of the corresponding trans orientation,more preferably, the compound of formula (XVI-A) is present in thecorresponding trans orientation; wherein the compound of formula (XVI-A)is preferably present in an amount in the range of from about 1.0 toabout 2.0 molar equivalents (relative to the moles of the compound offormula (XV-S)), more preferably in an amount in the range of from about1.0 to about 1.5 molar equivalents, more preferably still in an amountof about 1.1 to about 1.2 molar equivalents;

in the presence of CuI, and the like, wherein the CuI is preferablypresent in an amount in the range of from about 0.1 to about 1.0 molarequivalents, more preferably, in an amount in the range of from about0.1 to about 0.5 molar equivalents, more preferably in an amount ofabout 0.2 molar equivalents;

in the presence of an inorganic base, such as Cs₂CO₃, K₂CO₃, K₃PO₄, andthe like, preferably Cs₂CO₃; wherein the inorganic base is preferablypresent in an amount in the range of from about 0.5 to about 2.0 molarequivalents, more preferably, in an amount in the range of from about0.5 to about 3.0 molar equivalents, more preferably, in an amount ofabout 1.0 molar equivalents;

in the presence of a suitably selected ligand such asN,N-dimethylethylenediamine, N,N-dimethylglycine, dicyclohexyldiamine,and the like, preferably, N,N-dimethylethylenediamine; wherein theligand is preferably present in an amount in the range of from about 0.2to about 2.0 molar equivalents, more preferably, in an amount in therange of from about 0.2 to about 1.0 molar equivalents, more preferably,in an amount of about 0.4 molar equivalents;

in an organic solvent or mixtures thereof, such as DMA,N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and thelike, preferably DMA; preferably at a temperature in the range of fromabout 50° C. to about 100° C., preferably at about 75° C.; to yield thecorresponding compound of formula (XIX-A).

Preferably, the compound of formula (XV-S) is reacted with the compoundof formula (XVI-A) under an inert atmosphere, for example under nitrogenor argon. Preferably, a mixture of the compound of formula (XV-S), theCuI, the ligand, the inorganic base and the organic solvent is heated toa temperature in the range of from about 50° C. to about 100, to yield ahomogeneous mixture; prior to addition of the compound of formula(XVI-A).

Preferably, in the reaction of the compound of formula (XV-S) with thecompound of formula (XVI-A), the compound of formula (XVI-A) is presentin an excess of its geometrical isomer, more particularly, itscorresponding trans isomer, to yield the compound of formula (XIX-A) inits corresponding trans isomer. When the compound of formula (XV-S) isreacted with a compound of formula (XVI-A), wherein the compound offormula (XVI-A) is present in either its corresponding cis configurationor as a mixture of its corresponding cis and trans configurations, thenthe reaction proceeds to yield the compound of formula (XIX-A) as amixture of its corresponding cis and trans configurations.

The compound of formula (XIX-A) is de-protected according to knownmethods, to yield the corresponding compound of formula (I-B). Forexample, the compound of formula (XIX-A) may be reacted with a suitablyselected de-alkylating agent such as TMS-Br, TMS-I, Br₃, and the like;wherein the de-alkylating agent is preferably present in an amount ofabout 2.0 molar equivalents; in the presence of a proton scavenger suchas pyridine, N-methylmorpholine, proton sponge (i.e.N,N,N′,N′-tetramethyl-1,8-diaminonaphthalene), and the like, preferablypyridine; in an organic solvent such as acetonitrile, DCM, DCE, and thelike, preferably acetonitrile; preferably at a temperature in the rangeof from about 10° C. to about 30° C., more preferably at about 10° C.;to yield the corresponding compound of formula (I-B).

Alternatively, the compound of formula (XIX-A) may be reacted with asuitably selected de-alkylating agent such as TMS-Cl, and the like; inthe presence of NaI, and the like; in an organic solvent such asacetonitrile, and the like; to yield the corresponding compound offormula (I-B).

The present invention is further directed to a process for thepreparation of a compound of formula (I-C), as outlined in Scheme 12below.

Accordingly, a suitably substituted compound of formula (X-S), whereinPG¹ is a suitably substituted oxygen protecting group such as C₁₋₄alkyl,phenyl, benzyl, and the like, preferably, PG¹ is methyl, ethyl ort-butyl, more preferably, PG¹ is ethyl; is reacted according to any ofthe methods as described in Schemes 3 and 5 above; to yield thecorresponding compound of formula (XV-5).

The compound of formula (XV-S) is reacted with a suitably substitutedcompound of formula (XVI-A); wherein the compound of formula (XVI-A) ispreferably present in an excess of the corresponding trans orientation,more preferably, the compound of formula (XVI-A) is present in thecorresponding trans orientation; wherein the compound of formula (XVI-A)is preferably present in an amount in the range of from about 1.0 toabout 2.0 molar equivalents (relative to the moles of the compound offormula (XV-S)), more preferably in an amount in the range of from about1.0 to about 1.5 molar equivalents, more preferably still in an amountof about 1.1 to about 1.2 molar equivalents;

in the presence of CuI, and the like, wherein the CuI is preferablypresent in an amount in the range of from about 0.1 to about 1.0 molarequivalents, more preferably, in an amount in the range of from about0.1 to about 0.5 molar equivalents, more preferably in an amount ofabout 0.2 molar equivalents;

in the presence of an inorganic base, such as Cs₂CO₃, K₂CO₃, K₃PO₄, andthe like, preferably Cs₂CO₃; wherein the inorganic base is preferablypresent in an amount in the range of from about 0.5 to about 2.0 molarequivalents, more preferably, in an amount in the range of from about0.5 to about 3.0 molar equivalents, more preferably, in an amount ofabout 1.0 molar equivalents;

in the presence of a suitably selected ligand such asN,N-dimethylethylenediamine, N,N-dimethylglycine, dicyclohexyldiamine,and the like, preferably, N,N-dimethylethylenediamine; wherein theligand is preferably present in an amount in the range of from about 0.2to about 2.0 molar equivalents, more preferably, in an amount in therange of from about 0.2 to about 1.0 molar equivalents, more preferably,in an amount of about 0.4 molar equivalents;

in an organic solvent or mixtures thereof, such as DMA,N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and thelike, preferably DMA; preferably at a temperature in the range of fromabout 50° C. to about 100° C., preferably at about 75° C.; to yield thecorresponding compound of formula (XIX-A).

Preferably, the compound of formula (XV-S) is reacted with the compoundof formula (XVI-A) under an inert atmosphere, for example under nitrogenor argon. Preferably, a mixture of the compound of formula (XV-S), theCuI, the ligand, the inorganic base and the organic solvent is heated toa temperature in the range of from about 50° C. to about 100, to yield ahomogeneous mixture; prior to addition of the compound of formula(XVI-A).

Preferably, in the reaction of the compound of formula (XV-S) with thecompound of formula (XVI-A), the compound of formula (XVI-A) is presentin an excess of its geometrical isomer, more particularly, itscorresponding trans isomer, to yield the compound of formula (XIX-A) inits corresponding trans isomer. When the compound of formula (XV-S) isreacted with a compound of formula (XVI-A), wherein the compound offormula (XVI-A) is present in either its corresponding cis configurationor as a mixture of its corresponding cis and trans configurations, thenthe reaction proceeds to yield the compound of formula (XIX-A) as amixture of its corresponding cis and trans configurations.

The compound of formula (XIX-A) is de-protected according to knownmethods, to yield the corresponding compound of formula (I-B). Forexample, the compound of formula (XIX-A) may be reacted with a suitablyselected de-alkylating agent such as TMS-Br, TMS-I, Br₃, and the like;wherein the de-alkylating agent is preferably present in an amount ofabout 2.0 molar equivalents; in the presence of a proton scavenger suchas pyridine, N-methylmorpholine, proton sponge (i.e.N,N,N′,N′-tetramethyl-1,8-diaminonaphthalene), and the like, preferablypyridine; in an organic solvent such as acetonitrile, DCM, DCE, and thelike, preferably acetonitrile; preferably at a temperature in the rangeof from about 10° C. to about 30° C., more preferably at about 10° C.;to yield the corresponding compound of formula (I-B).

Alternatively, the compound of formula (XIX-A) may be reacted with asuitably selected de-alkylating agent such as TMS-Cl, and the like; inthe presence of NaI, and the like; in an organic solvent such asacetonitrile, and the like; to yield the corresponding compound offormula (I-B).

The compound of formula (I-B) is reacted with a suitably substitutedcompound of formula (XVIII-A), wherein Q¹ is a suitably selected leavinggroup such as Br, Cl, I, and the like, preferably Cl, a known compoundor compound prepared by known methods; wherein the compound of formula(XVIII-A) is preferably present in an amount in the range of from about1.0 to about 3.0 molar equivalents, more preferably about 1.7 molarequivalents; in the presence of an organic base such as DIPEA, TEA,pyridine, and the like, preferably DIPEA; wherein the organic base ispreferably present in an amount in the range of from about 1.5 to about5.0 molar equivalents; more preferably about 2.0 molar equivalents; inan organic solvent such DMF and the like; preferably at a temperature inthe range of from about 50° C. to about 120° C., more preferably atabout 73° C.; to yield the corresponding compound of formula (X-C).

The present invention is further directed to a process for thepreparation of a compound of formula (I-D) as outlined in Scheme 13below.

Accordingly, a suitably substituted compound of formula (X-S), whereinPG¹ is a suitably substituted oxygen protecting group such as C₁₋₄alkyl,phenyl, benzyl, and the like, preferably, PG¹ is methyl, ethyl ort-butyl, more preferably, PG¹ is ethyl; is reacted according to any ofthe methods as described in Schemes 3 and 5, above; to yield thecorresponding compound of formula (XV-S).

The compound of formula (XV-S) is reacted with a suitably substitutedcompound of formula (XVI-A); wherein the compound of formula (XVI-A) ispreferably present in an excess of the corresponding trans orientation,more preferably, the compound of formula (XVI-A) is present in thecorresponding trans orientation; wherein the compound of formula (XVI-A)is preferably present in an amount in the range of from about 1.0 toabout 2.0 molar equivalents (relative to the moles of the compound offormula (XV-S)), more preferably in an amount in the range of from about1.0 to about 1.5 molar equivalents, more preferably still in an amountof about 1.1 to about 1.2 molar equivalents;

in the presence of CuI, and the like, wherein the CuI is preferablypresent in an amount in the range of from about 0.1 to about 1.0 molarequivalents, more preferably, in an amount in the range of from about0.1 to about 0.5 molar equivalents, more preferably in an amount ofabout 0.2 molar equivalents;

in the presence of an inorganic base, such as Cs₂CO₃, K₂CO₃, K₃PO₄, andthe like, preferably Cs₂CO₃; wherein the inorganic base is preferablypresent in an amount in the range of from about 0.5 to about 2.0 molarequivalents, more preferably, in an amount in the range of from about0.5 to about 3.0 molar equivalents, more preferably, in an amount ofabout 1.0 molar equivalents;

in the presence of a suitably selected ligand such asN,N-dimethylethylenediamine, N,N-dimethylglycine, dicyclohexyldiamine,and the like, preferably, N,N-dimethylethylenediamine; wherein theligand is preferably present in an amount in the range of from about 0.2to about 2.0 molar equivalents, more preferably, in an amount in therange of from about 0.2 to about 1.0 molar equivalents, more preferably,in an amount of about 0.4 molar equivalents;

in an organic solvent or mixtures thereof, such as DMA,N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and thelike, preferably DMA; preferably at a temperature in the range of fromabout 50° C. to about 100° C., preferably at about 75° C.; to yield thecorresponding compound of formula (XIX-A).

Preferably, the compound of formula (XV-S) is reacted with the compoundof formula (XVI-A) under an inert atmosphere, for example under nitrogenor argon. Preferably, a mixture of the compound of formula (XV-S), theCuI, the ligand, the inorganic base and the organic solvent is heated toa temperature in the range of from about 50° C. to about 100, to yield ahomogeneous mixture; prior to addition of the compound of formula(XVI-A).

Preferably, in the reaction of the compound of formula (XV-S) with thecompound of formula (XVI-A), the compound of formula (XVI-A) is presentin an excess of its geometrical isomer, more particularly, itscorresponding trans isomer, to yield the compound of formula (XIX-A) inits corresponding trans isomer. When the compound of formula (XV-S) isreacted with a compound of formula (XVI-A), wherein the compound offormula (XVI-A) is present in either its corresponding cis configurationor as a mixture of its corresponding cis and trans configurations, thenthe reaction proceeds to yield the compound of formula (XIX-A) as amixture of its corresponding cis and trans configurations.

The compound of formula (XIX-A) is de-protected according to knownmethods, to yield the corresponding compound of formula (I-B). Forexample, the compound of formula (XIX-A) may be reacted with a suitablyselected de-alkylating agent such as TMS-Br, TMS-I, Br₃, and the like;wherein the de-alkylating agent is preferably present in an amount ofabout 2.0 molar equivalents; in the presence of a proton scavenger suchas pyridine, N-methylmorpholine, proton sponge (i.e.N,N,N′,N′-tetramethyl-1,8-diaminonaphthalene), and the like, preferablypyridine; in an organic solvent such as acetonitrile, DCM, DCE, and thelike, preferably acetonitrile; preferably at a temperature in the rangeof from about 10° C. to about 30° C., more preferably at about 10° C.;to yield the corresponding compound of formula (I-B).

Alternatively, the compound of formula (XIX-A) may be reacted with asuitably selected de-alkylating agent such as TMS-Cl, and the like; inthe presence of NaI, and the like; in an organic solvent such asacetonitrile, and the like; to yield the corresponding compound offormula (I-B).

The compound of formula (I-B) is reacted with a suitably substitutedcompound of formula (XVIII-B), wherein Q¹ is a suitably selected leavinggroup such as Br, Cl, I, and the like, preferably Cl, a known compoundor compound prepared by known methods; wherein the compound of formula(XVIII-B) is preferably present in an amount in the range of from about1.0 to about 3.0 molar equivalents, more preferably about 1.7 molarequivalents; in the presence of an organic base such as DIPEA, TEA,pyridine, and the like, preferably DIPEA; wherein the organic base ispreferably present in an amount in the range of from about 1.5 to about5.0 molar equivalents; more preferably about 2.0 molar equivalents; inan organic solvent such DMF and the like; preferably at a temperature inthe range of from about 50° C. to about 120° C., more preferably atabout 73° C.; to yield the corresponding compound of formula (I-D).

The present invention is further directed to a process for thepreparation of a compound of formula (I-E), as outlined in Scheme 14below.

Accordingly, a suitably substituted compound of formula (IV-S), whereinPG¹ is a suitably substituted oxygen protecting group such as C₁₋₄alkyl,phenyl, benzyl, and the like, preferably, PG¹ is methyl, ethyl ort-butyl, more preferably, PG¹ is ethyl; is reacted according to any ofthe methods as described in Scheme 2 and 4 above; to yield thecorresponding compound of formula (IX-S).

The compound of formula (IX-S) is reacted with a suitably substitutedcompound of formula (XVI-B); wherein the compound of formula (XVI-B) ispreferably present in an excess of the corresponding trans orientation,more preferably, the compound of formula (XVI-B) is present in thecorresponding trans orientation; wherein the compound of formula (XVI-B)is preferably present in an amount in the range of from about 1.0 toabout 2.0 molar equivalents (relative to the moles of the compound offormula (IX-S)), more preferably in an amount in the range of from about1.0 to about 1.5 molar equivalents, more preferably still in an amountof about 1.1 to about 1.2 molar equivalents;

in the presence of CuI, and the like, wherein the CuI is preferablypresent in an amount in the range of from about 0.1 to about 1.0 molarequivalents, more preferably, in an amount in the range of from about0.1 to about 0.5 molar equivalents, more preferably in an amount ofabout 0.2 molar equivalents;

in the presence of an inorganic base, such as Cs₂CO₃, K₂CO₃, K₃PO₄, andthe like, preferably Cs₂CO₃; wherein the inorganic base is preferablypresent in an amount in the range of from about 0.5 to about 2.0 molarequivalents, more preferably, in an amount in the range of from about0.5 to about 3.0 molar equivalents, more preferably, in an amount ofabout 1.0 molar equivalents;

in the presence of a suitably selected ligand such asN,N-dimethylethylenediamine, N,N-dimethylglycine, dicyclohexyldiamine,and the like, preferably, N,N-dimethylethylenediamine; wherein theligand is preferably present in an amount in the range of from about 0.2to about 2.0 molar equivalents, more preferably, in an amount in therange of from about 0.2 to about 1.0 molar equivalents, more preferably,in an amount of about 0.4 molar equivalents;

in an organic solvent or mixtures thereof, such as DMA,N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and thelike, preferably DMA; preferably at a temperature in the range of fromabout 50° C. to about 100° C., preferably at about 75° C.; to yield thecorresponding compound of formula (XVII-B).

Preferably, the compound of formula (IX-S) is reacted with the compoundof formula (XVI-B) under an inert atmosphere, for example under nitrogenor argon. Preferably, a mixture of the compound of formula (IX-S), theCuI, the ligand, the inorganic base and the organic solvent is heated toa temperature in the range of from about 50° C. to about 100, to yield ahomogeneous mixture; prior to addition of the compound of formula(XVI-B).

Preferably, in the reaction of the compound of formula (IX-S) with thecompound of formula (XVI-B), the compound of formula (XVI-B) is presentin an excess of its geometrical isomer, more particularly, itscorresponding trans isomer, to yield the compound of formula (XVII-B) inits corresponding trans isomer. When the compound of formula (IX-S) isreacted with a compound of formula (XVI-B), wherein the compound offormula (XVI-B) is present in either its corresponding cis configurationor as a mixture of its corresponding cis and trans configurations, thenthe reaction proceeds to yield the compound of formula (XVII-B) as amixture of its corresponding cis and trans configurations.

The compound of formula (XVII-B) is de-protected according to knownmethods, to yield the corresponding compound of formula (I-E). Forexample, the compound of formula (XVII-B) may be reacted with a suitablyselected de-alkylating agent such as TMS-Br, TMS-1, Br₃, and the like;wherein the de-alkylating agent is preferably present in an amount ofabout 2.0 molar equivalents; in the presence of a proton scavenger suchas pyridine, N-methylmorpholine, proton sponge (i.e.N,N,N′,N′-tetramethyl-1,8-diaminonaphthalene), and the like, preferablypyridine; in an organic solvent such as acetonitrile, DCM, DCE, and thelike, preferably acetonitrile; preferably at a temperature in the rangeof from about 10° C. to about 30° C., more preferably at about 10° C.;to yield the corresponding compound of formula (I-E).

Alternatively, the compound of formula (XVII-B) may be reacted with asuitably selected de-alkylating agent such as TMS-Cl, and the like; inthe presence of NaI, and the like; in an organic solvent such asacetonitrile, and the like; to yield the corresponding compound offormula (I-E).

The present invention is further directed to a process for thepreparation of a compound of formula (I-F), as outlined in Scheme 15below.

Accordingly, a suitably substituted compound of formula (X-S), whereinPG¹ is a suitably substituted oxygen protecting group such as C₁₋₄alkyl,phenyl, benzyl, and the like, preferably, PG¹ is methyl, ethyl ort-butyl, more preferably, PG¹ is ethyl; is reacted according to any ofthe methods as described in Schemes 3 and 5 above; to yield thecorresponding compound of formula (XV-S).

The compound of formula (XV-S) is reacted with a suitably substitutedcompound of formula (XVI-B); wherein the compound of formula (XVI-B) ispreferably present in an excess of the corresponding trans orientation,more preferably, the compound of formula (XVI-B) is present in thecorresponding trans orientation; wherein the compound of formula (XVI-B)is preferably present in an amount in the range of from about 1.0 toabout 2.0 molar equivalents (relative to the moles of the compound offormula (X-B)), more preferably in an amount in the range of from about1.0 to about 1.5 molar equivalents, more preferably still in an amountof about 1.1 to about 1.2 molar equivalents;

in the presence of CuI, and the like, wherein the CuI is preferablypresent in an amount in the range of from about 0.1 to about 1.0 molarequivalents, more preferably, in an amount in the range of from about0.1 to about 0.5 molar equivalents, more preferably in an amount ofabout 0.2 molar equivalents;

in the presence of an inorganic base, such as Cs₂CO₃, K₂CO₃, K₃PO₄, andthe like, preferably Cs₂CO₃; wherein the inorganic base is preferablypresent in an amount in the range of from about 0.5 to about 2.0 molarequivalents, more preferably, in an amount in the range of from about0.5 to about 3.0 molar equivalents, more preferably, in an amount ofabout 1.0 molar equivalents;

in the presence of a suitably selected ligand such asN,N-dimethylethylenediamine, N,N-dimethylglycine, dicyclohexyldiamine,and the like, preferably, N,N-dimethylethylenediamine; wherein theligand is preferably present in an amount in the range of from about 0.2to about 2.0 molar equivalents, more preferably, in an amount in therange of from about 0.2 to about 1.0 molar equivalents, more preferably,in an amount of about 0.4 molar equivalents;

in an organic solvent or mixtures thereof, such as DMA,N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and thelike, preferably DMA; preferably at a temperature in the range of fromabout 50° C. to about 100° C., preferably at about 75° C.; to yield thecorresponding compound of formula (XIX-B).

Preferably, the compound of formula (XV-S) is reacted with the compoundof formula (XVI-B) under an inert atmosphere, for example under nitrogenor argon. Preferably, a mixture of the compound of formula (XV-S), theCuI, the ligand, the inorganic base and the organic solvent is heated toa temperature in the range of from about 50° C. to about 100, to yield ahomogeneous mixture; prior to addition of the compound of formula(XVI-B).

Preferably, in the reaction of the compound of formula (XV-S) with thecompound of formula (XVI-B), the compound of formula (XVI-B) is presentin an excess of its geometrical isomer, more particularly, itscorresponding trans isomer, to yield the compound of formula (XIX-B) inits corresponding trans isomer. When the compound of formula (XV-S) isreacted with a compound of formula (XVI-B), wherein the compound offormula (XVI-B) is present in either its corresponding cis configurationor as a mixture of its corresponding cis and trans configurations, thenthe reaction proceeds to yield the compound of formula (XIX-B) as amixture of its corresponding cis and trans configurations.

The compound of formula (XIX-B) is de-protected according to knownmethods, to yield the corresponding compound of formula (I-F). Forexample, the compound of formula (XIX-B) may be reacted with a suitablyselected de-alkylating agent such as TMS-Br, TMS-I, Br₃, and the like;wherein the de-alkylating agent is preferably present in an amount ofabout 2.0 molar equivalents; in the presence of a proton scavenger suchas pyridine, N-methylmorpholine, proton sponge (i.e.N,N,N′,N′-tetramethyl-1,8-diaminonaphthalene), and the like, preferablypyridine; in an organic solvent such as acetonitrile, DCM, DCE, and thelike, preferably acetonitrile; preferably at a temperature in the rangeof from about 10° C. to about 30° C., more preferably at about 10° C.;to yield the corresponding compound of formula (I-F).

Alternatively, the compound of formula (XIX-B) may be reacted with asuitably selected de-alkylating agent such as TMS-Cl, and the like; inthe presence of NaI, and the like; in an organic solvent such asacetonitrile, and the like; to yield the corresponding compound offormula (I-F).

The present invention is further directed to a process for thepreparation of a compound of formula (I-G), as outlined in Scheme 16below.

Accordingly, a suitably substituted compound of formula (X-S), whereinPG¹ is a suitably substituted oxygen protecting group such as C₁₋₄alkyl,phenyl, benzyl, and the like, preferably, PG¹ is methyl, ethyl ort-butyl, more preferably, PG¹ is ethyl; is reacted according to any ofthe methods as described in Schemes 3 and 5 above; to yield thecorresponding compound of formula (XV-5).

The compound of formula (XV-S) is reacted with a suitably substitutedcompound of formula (XVI-B); wherein the compound of formula (XVI-B) ispreferably present in an excess of the corresponding trans orientation,more preferably, the compound of formula (XVI-B) is present in thecorresponding trans orientation; wherein the compound of formula (XVI-B)is preferably present in an amount in the range of from about 1.0 toabout 2.0 molar equivalents (relative to the moles of the compound offormula (X-B)), more preferably in an amount in the range of from about1.0 to about 1.5 molar equivalents, more preferably still in an amountof about 1.1 to about 1.2 molar equivalents;

in the presence of CuI, and the like, wherein the CuI is preferablypresent in an amount in the range of from about 0.1 to about 1.0 molarequivalents, more preferably, in an amount in the range of from about0.1 to about 0.5 molar equivalents, more preferably in an amount ofabout 0.2 molar equivalents;

in the presence of an inorganic base, such as Cs₂CO₃, K₂CO₃, K₃PO₄, andthe like, preferably Cs₂CO₃; wherein the inorganic base is preferablypresent in an amount in the range of from about 0.5 to about 2.0 molarequivalents, more preferably, in an amount in the range of from about0.5 to about 3.0 molar equivalents, more preferably, in an amount ofabout 1.0 molar equivalents;

in the presence of a suitably selected ligand such asN,N-dimethylethylenediamine, N,N-dimethylglycine, dicyclohexyldiamine,and the like, preferably, N,N-dimethylethylenediamine; wherein theligand is preferably present in an amount in the range of from about 0.2to about 2.0 molar equivalents, more preferably, in an amount in therange of from about 0.2 to about 1.0 molar equivalents, more preferably,in an amount of about 0.4 molar equivalents;

in an organic solvent or mixtures thereof, such as DMA,N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and thelike, preferably DMA; preferably at a temperature in the range of fromabout 50° C. to about 100° C., preferably at about 75° C.; to yield thecorresponding compound of formula (XIX-B).

Preferably, the compound of formula (XV-S) is reacted with the compoundof formula (XVI-B) under an inert atmosphere, for example under nitrogenor argon. Preferably, a mixture of the compound of formula (XV-S), theCuI, the ligand, the inorganic base and the organic solvent is heated toa temperature in the range of from about 50° C. to about 100, to yield ahomogeneous mixture; prior to addition of the compound of formula(XVI-B).

Preferably, in the reaction of the compound of formula (XV-S) with thecompound of formula (XVI-B), the compound of formula (XVI-B) is presentin an excess of its geometrical isomer, more particularly, itscorresponding trans isomer, to yield the compound of formula (XIX-B) inits corresponding trans isomer. When the compound of formula (XV-S) isreacted with a compound of formula (XVI-B), wherein the compound offormula (XVI-B) is present in either its corresponding cis configurationor as a mixture of its corresponding cis and trans configurations, thenthe reaction proceeds to yield the compound of formula (XIX-B) as amixture of its corresponding cis and trans configurations.

The compound of formula (XIX-B) is de-protected according to knownmethods, to yield the corresponding compound of formula (I-F). Forexample, the compound of formula (XIX-B) may be reacted with a suitablyselected de-alkylating agent such as TMS-Br, TMS-I, Br₃, and the like;wherein the de-alkylating agent is preferably present in an amount ofabout 2.0 molar equivalents; in the presence of a proton scavenger suchas pyridine, N-methylmorpholine, proton sponge (i.e.N,N,N′,N′-tetramethyl-1,8-diaminonaphthalene), and the like, preferablypyridine; in an organic solvent such as acetonitrile, DCM, DCE, and thelike, preferably acetonitrile; preferably at a temperature in the rangeof from about 10° C. to about 30° C., more preferably at about 10° C.;to yield the corresponding compound of formula (I-F).

Alternatively, the compound of formula (XIX-B) may be reacted with asuitably selected de-alkylating agent such as TMS-Cl, and the like; inthe presence of NaI, and the like; in an organic solvent such asacetonitrile, and the like; to yield the corresponding compound offormula (I-F).

The compound of formula (I-F) is reacted with a suitably substitutedcompound of formula (XVIII-A), wherein Q¹ is a suitably selected leavinggroup such as Br, Cl, I, and the like, preferably Cl, a known compoundor compound prepared by known methods; wherein the compound of formula(XVIII-A) is preferably present in an amount in the range of from about1.0 to about 3.0 molar equivalents, more preferably about 1.7 molarequivalents; in the presence of an organic base such as DIPEA, TEA,pyridine, and the like, preferably DIPEA; wherein the organic base ispreferably present in an amount in the range of from about 1.5 to about5.0 molar equivalents; more preferably about 2.0 molar equivalents; inan organic solvent such DMF and the like; preferably at a temperature inthe range of from about 50° C. to about 120° C., more preferably atabout 73° C.; to yield the corresponding compound of formula (I-G).

The present invention is further directed to a process for thepreparation of a compound of formula (X-H), as outlined in Scheme 17below.

Accordingly, a suitably substituted compound of formula (X-S), whereinPG¹ is a suitably substituted oxygen protecting group such as C₁₋₄alkyl,phenyl, benzyl, and the like, preferably, PG¹ is methyl, ethyl ort-butyl, more preferably, PG¹ is ethyl; is reacted according to any ofthe methods as described in Schemes 3 and 5 above; to yield thecorresponding compound of formula (XV-S).

The compound of formula (XV-S) is reacted with a suitably substitutedcompound of formula (XVI-B); wherein the compound of formula (XVI-B) ispreferably present in an excess of the corresponding trans orientation,more preferably, the compound of formula (XVI-B) is present in thecorresponding trans orientation; wherein the compound of formula (XVI-B)is preferably present in an amount in the range of from about 1.0 toabout 2.0 molar equivalents (relative to the moles of the compound offormula (X-B)), more preferably in an amount in the range of from about1.0 to about 1.5 molar equivalents, more preferably still in an amountof about 1.1 to about 1.2 molar equivalents;

in the presence of CuI, and the like, wherein the CuI is preferablypresent in an amount in the range of from about 0.1 to about 1.0 molarequivalents, more preferably, in an amount in the range of from about0.1 to about 0.5 molar equivalents, more preferably in an amount ofabout 0.2 molar equivalents;

in the presence of an inorganic base, such as Cs₂CO₃, K₂CO₃, K₃PO₄, andthe like, preferably Cs₂CO₃; wherein the inorganic base is preferablypresent in an amount in the range of from about 0.5 to about 2.0 molarequivalents, more preferably, in an amount in the range of from about0.5 to about 3.0 molar equivalents, more preferably, in an amount ofabout 1.0 molar equivalents;

in the presence of a suitably selected ligand such asN,N-dimethylethylenediamine, N,N-dimethylglycine, dicyclohexyldiamine,and the like, preferably, N,N-dimethylethylenediamine; wherein theligand is preferably present in an amount in the range of from about 0.2to about 2.0 molar equivalents, more preferably, in an amount in therange of from about 0.2 to about 1.0 molar equivalents, more preferably,in an amount of about 0.4 molar equivalents;

in an organic solvent or mixtures thereof, such as DMA,N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and thelike, preferably DMA; preferably at a temperature in the range of fromabout 50° C. to about 100° C., preferably at about 75° C.; to yield thecorresponding compound of formula (XIX-B).

Preferably, the compound of formula (XV-S) is reacted with the compoundof formula (XVI-B) under an inert atmosphere, for example under nitrogenor argon. Preferably, a mixture of the compound of formula (XV-S), theCuI, the ligand, the inorganic base and the organic solvent is heated toa temperature in the range of from about 50° C. to about 100, to yield ahomogeneous mixture; prior to addition of the compound of formula(XVI-B).

Preferably, in the reaction of the compound of formula (XV-S) with thecompound of formula (XVI-B), the compound of formula (XVI-B) is presentin an excess of its geometrical isomer, more particularly, itscorresponding trans isomer, to yield the compound of formula (XIX-B) inits corresponding trans isomer. When the compound of formula (XV-S) isreacted with a compound of formula (XVI-B), wherein the compound offormula (XVI-B) is present in either its corresponding cis configurationor as a mixture of its corresponding cis and trans configurations, thenthe reaction proceeds to yield the compound of formula (XIX-B) as amixture of its corresponding cis and trans configurations.

The compound of formula (XIX-B) is de-protected according to knownmethods, to yield the corresponding compound of formula (I-F). Forexample, the compound of formula (XIX-B) may be reacted with a suitablyselected de-alkylating agent such as TMS-Br, TMS-I, Br₃, and the like;wherein the de-alkylating agent is preferably present in an amount ofabout 2.0 molar equivalents; in the presence of a proton scavenger suchas pyridine, N-methylmorpholine, proton sponge (i.e.N,N,N′,N′-tetramethyl-1,8-diaminonaphthalene), and the like, preferablypyridine; in an organic solvent such as acetonitrile, DCM, DCE, and thelike, preferably acetonitrile; preferably at a temperature in the rangeof from about 10° C. to about 30° C., more preferably at about 10° C.;to yield the corresponding compound of formula (I-F).

Alternatively, the compound of formula (XIX-B) may be reacted with asuitably selected de-alkylating agent such as TMS-Cl, and the like; inthe presence of NaI, and the like; in an organic solvent such asacetonitrile, and the like; to yield the corresponding compound offormula (I-F).

The compound of formula (I-F) is reacted with a suitably substitutedcompound of formula (XVIII-B), wherein Q¹ is a suitably selected leavinggroup such as Br, Cl, I, and the like, preferably Cl, a known compoundor compound prepared by known methods; wherein the compound of formula(XVIII-B) is preferably present in an amount in the range of from about1.0 to about 3.0 molar equivalents, more preferably about 1.7 molarequivalents; in the presence of an organic base such as DIPEA, TEA,pyridine, and the like, preferably DIPEA; wherein the organic base ispreferably present in an amount in the range of from about 1.5 to about5.0 molar equivalents; more preferably about 2.0 molar equivalents; inan organic solvent such DMF and the like; preferably at a temperature inthe range of from about 50° C. to about 120° C., more preferably atabout 73° C.; to yield the corresponding compound of formula (I-H).

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products are listed ashaving been isolated as a residue. It will be understood by one ofordinary skill in the art that the term “residue” does not limit thephysical state in which the product was isolated and may include, forexample, a solid, an oil, a foam, a gum, a syrup, and the like.

Example 1{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinicacid ethyl ester

Cesium Carbonate Method:

A 3 L 4-necked round-bottomed flask equipped with addition funnel,mechanical stirrer, nitrogen inlet, heating mantle and thermocouple wascharged with[carbamoyl-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-methyl-phosphinicacid ethyl ester (100 g, 0.3 mol), Cs₂CO₃ (58.6 g, 0.18 mol),N,N-dimethylacetamide (DMA) (300 mL, anhydrous 99.8%),N,N′-dimethyl-ethylenediamine (10.6 g, 0.12 mol) and copper (I) iodide(11.4 g, 0.06 mol) and the resulting mixture heated to about 80° C.,under nitrogen. To the resulting mixture was then added a solution of4-(2-bromo-vinyl)-1,2-difluoro-benzene (78.8 g, 0.36 mol) in DMA (30mL), slowly over a period of about 20 min and the resulting mixturestirred at this temperature for 5 hours. The resulting mixture was thenquenched while hot with H₂O (600 mL), and diluted with EtOAc (700 mL),added slowly through an addition funnel. The resulting biphasic mixturewas cooled to 50-55° C. and at this temperature the layers wereseparated. The organic layer was washed with H₂O (500 mL), 0.5N HClaqueous solution (500 mL) and brine (500 mL), then filtered andconcentrated under reduced pressure to approximately half the originalvolume (350-400 mL). The concentrated solution was heated to slowreflux. Heptane (250 mL) was then added slowly at this temperature. Theresulting suspension was cooled to 5-10° C. over a period of 1 hr,diluted with additional heptane (100 mL) and aged at this temperaturefor a period of about 2 hrs. The resulting solid precipitate wasfiltered, rinsed with cold heptane/EtOAc (4/1) solvent mixture (100 ml),and dried at 55° C. in a vacuum oven overnight, to yield the titlecompound as a white solid.

HPLC on a sample of the isolated product indicated 95% purity.

Example 2{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinicacid ethyl ester

Potassium Carbonate Method:

A 3 L 4-necked round-bottomed flask equipped with addition funnel,mechanical stirrer, nitrogen inlet, heating mantle and thermocouple wascharged with[carbamoyl-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-methyl-phosphinicacid ethyl ester (10.5 g, 0.03 mol), K₂CO₃ (8.0 g, 0.03 mol),N,N-dimethylacetamide (DMA) (40 mL, anhydrous 99.8%),N,N′-dimethyl-ethylenediamine (1.6 g, 0.018 mol) and copper (I) iodide(1.14 g, 0.006 mol) and the resulting mixture heated to about 80° C.under nitrogen. To the resulting mixture was then added4-(2-bromo-vinyl)-1,2-difluoro-benzene (7.9 g, 0.036 mol) slowly, over aabout 20 minutes, at 80° C. and the resulting mixture stirred at thistemperature for about 5 hours. The resulting mixture was then quenchedwhile hot with H₂O (60 mL), and diluted with EtOAc (70 mL), added slowlythrough an addition funnel. The resulting biphasic mixture was cooled to50-55° C. and at this temperature the layers were separated. The organiclayer was washed with H₂O (50 mL), 0.5N HCl aq.solution (50 mL) andbrine (50 mL), then filtered and concentrated under reduced pressure toabout half the original volume (35-40 mL). The concentrated solution washeated to slow reflux and then heptane (25 mL) was added slowly at thistemperature. The resulting suspension was cooled to 5-10° C. over aperiod of 1 hr, diluted with additional heptane (10 mL) and aged at thistemperature for about 2 hrs. The resulting solid precipitate wasfiltered, rinsed with cold heptane/EtOAc (4/1) solvent mixture (10 ml),and dried 55° C. in a vacuum oven overnight, to yield the title compoundas a white solid.

HPLC on a sample of the isolated product indicated 95% purity.

Example 3{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinicacid

A 1 L four-necked round-bottomed flask equipped with mechanical stirrer,addition funnel, condenser, and a thermocouple was charged with{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]methyl}-methyl-phosphinicacid ethyl ester (26.4 g, 0.056 mol), acetonitrile (200 mL) and pyridine(11.0 mL, 0.136 mol). To the resulting mixture was then addedbromotrimethylsilane (15.5 mL, 0.117 mol), 15 minutes, while maintainingthe temperature of the resulting mixture below about 30° C. The mixturewas then stirred for an additional 15 minutes to yield a clear yellowsolution, which was aged for about 2 hours. The resulting mixture wasthen cooled to about 0-5° C. To the mixture was then added concentratedsulfuric acid (5.4 mL) in water (90 mL), using vigorous agitation. Tothe resulting mixture was then added MTBE (150 mL) and the mixture agedwith stirring until two homogeneous layers were obtained. The layerswere separated and the organic layer was washed twice with water (45 mL)and then concentrated to yield a residue. The residue was digested withmethanol (180 mL) under vigorous stirring. then concentrated to about50% of its original volume under reduced pressure. The resulting slurrywas cooled to about 0-5° C., then aged at this temperature for about 1hours.

The resulting solids were filtered, washed twice with cold methanol (18mL), dried in a vacuum oven at 50° C., overnight, to yield the titlecompound as a white crystalline solid

Example 4{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinicacid Choline Salt

A 250 mL three-necked round-bottomed flask was charged with{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinicacid (20.0 g, 42.2 mol) and methanol (150 mL), under nitrogen. To theresulting slurry was then added 45% by wt. of choline hydroxide inmethanol (12.8 mL, 45.3 mol), in one portion. Shortly after theaddition, a homogeneous clear solution was obtained. The solution wasaged at room temperature for about 1 hour, then clarified by filtrationthrough a medium sintered glass filter. The resulting filtered solutionwas concentrated by distillation (at a temperature of about 63-65° C.)to a residual volume of about 55-60 mL. While at the elevatedtemperature, EtOAc (140-150 mL) was added by an addition funnel over aperiod of about 40 minutes, while maintaining a temperature of about63-65° C. The resulting clear solution was seeded, then cooled slowlyunder moderate agitation to ambient temperature. The resulting slurrywas then aged overnight, cooled to about 5-10° C. and aged at thistemperature for about 2 hours. The resulting solid was collected byfiltration, rinsed with cold EtOAc (40 mL, 2C) and dried in a vacuumoven at 50° C., overnight to yield the title compound as a whitecrystalline solid.

Example 5 4-(2-Bromo-vinyl)-1,2-difluoro-benzene

Method 1: (Adapted from the chemistry described in J. Org. Chem. 1997,62, pp 199-200)

3,4-Difluorocinnamic acid (1.8 g, 10 mmol) was combined withacetonitrile (18.6 mL) and water (1.4 mL) and the resulting mixturetreated with lithium acetate (0.12 g) and then N-bromosuccinimide (1.9g). The resulting solution was then heated to about 70° C. and stirredat that temperature for about 2 hours. The resulting mixture was thencooled to 25° C. and quenched with 5% sodium thiosulfate solution (about5 mL). The resulting mixture was extracted with heptane (2×30 mL) andthe combined heptane layers were rinsed with water, dried over magnesiumsulfate and the solvent evaporated to dryness to yield the titlecompound as a residue.

The ¹H NMR was measured for a sample of the residue, which wasdetermined to be a mixture of about 9:1 trans:cis isomers.

¹H NMR (CDCl₃): δ 7.21 (m, 3H), 6.60 (d, 1H, J=11.5 Hz), 6.39 (d, 1H,J=11.5 Hz)

Example 6 4-(2-Bromo-vinyl)-1,2-difluoro-benzene

Method 2: (Adapted from the chemistry described in Synlett 2000, 10 pp1439)

3,4-Difluorocinnamic acid (0.9 g, 5 mmol), lithium acetate (0.60 mg),N-bromosuccinimide (0.95 g), acetonitrile (9.3 mL) and water (0.7 mL)were placed in a microwave test tube and the resulting mixture washeated under microwave radiation for about 2 minutes. The resultingmixture was then cooled to ambient temperature and quenched with 5%sodium thiosulfate solution (about 2 mL). The resulting mixture was thenextracted with heptane (2×10 mL), the combined organics dried overmagnesium sulfate, and then concentrated under reduced pressure to yieldthe title compound as a residue.

The ¹H NMR was measured for a sample of the residue, which wasdetermined to be a mixture of about 9:1 trans:cis isomers.

¹H NMR (CDCl₃): δ 7.21 (m, 3H), 6.60 (d, 1H, J=11.5 Hz), 6.39 (d, 1H,J=11.5 Hz)

Example 7 4-(2-Bromo-vinyl)-1,2-difluoro-benzene

Method 3: (Adapted from the chemistry described in Tet. Lett. 1996, 37,pp 2623-2624)

3,4-Difluorocinnamic acid (1.8 g, 10 mmol) was combined withacetonitrile (8 mL0 and water (8 mL) and the resulting mixture wastreated first with Mn(OAc)₂ hydrate (0.49 g) and then with NBS (1.9 g).The resulting mixture was then heated to about 50° C. and stirred atthis temperature for about 16 hours. The resulting mixture was thencooled to about 25° C. and then quenched with 5% sodium thiosulfatesolution (about 5 mL). The resulting mixture was extracted with heptane(2×30 mL) and the combined heptane layers were rinsed with water, driedover magnesium sulfate and the solvent evaporated to dryness to yieldthe title compound a residue.

The ¹H NMR was measured for a sample of the residue, which wasdetermined to be a mixture of about 20:1 trans:cis isomers.

¹H NMR (CDCl₃): δ 7.21 (m, 3H), 6.60 (d, 1H, J=11.5 Hz), 6.39 (d, 1H,J=11.5 Hz)

Example 8[Carbamoyl-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-methyl-phosphinicacid ethyl ester

STEP A:Ethyl-1-(5-chlorobenzo[b]thiophen-3-yl)-2-oxoethyl-(methyl)-phosphinate-2-carboxylicacid

To a dry 4N 3000 ml flask equipped with mechanical stirrer, nitrogeninlet, temperature probe and addition port was added ethyl(5-chlorobenzo[b]thiophen-3-yl)methyl(methyl)phosphinate (95.0 g, 329mmol) and THF (100 mL), under nitrogen and the resulting solutin cooledto −20° C. To the resulting mixture was then added 20% 1.06M LiHMDSsolution in THF (500 ml), while maintaining the temperature below 10° C.Into the resulting mixture, while maintaining the mixture temperatureunder 15° C., was continuously bubbled CO₂ until no exotherm wasobserved. The resulting mixture was then aged for 1 hour. Following theage, the resulting mixture was cooled to −10° C. and additional LiHMDSsolution (100 ml) was added, followed by additional bubbled CO₂. Theresulting mixture again cooled to −10° C., additional LiHMDS solution(100 ml) was added, followed by additional bubbled CO₂. The resultingmixture was allowed to warm to room temperature, aged at roomtemperature for 2 hours, then cooled to 4° C. 2N HCl was added (500 ml)slowly to maintain the cold temperature and the resulting precipitatewas aged for 1 hour, at which time it was filtered and washed with water(100 mL). Filtration took approximately 1 hour. The resulting gelatinoussolid was allowed to air dry for about 24 hours over which time thematerial slowly turned to a compact white solid. The solid was treatedwith 1N HCl (500 mL) and MTBE (500 mL) and the resulting slurry digestedfor 2 hours. The resulting easily filterable dense solid was isolated,washed with 1:1=1N HCl:MTBE (100 ml) and the solid dried for 72 hours at50° C. under vacuum and nitrogen purge, to yieldethyl-1-(5-chlorobenzo[b]thiophen-3-yl)-2-oxoethyl(methyl)phosphinate-2-carboxylicacid as a solid.

STEP B:[Carbamoyl-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-methyl-phosphinicacid ethyl ester

A 2 L RBF with mechanical stirrer, addition port, temperature probe andnitrogen inlet was charged withethyl-1-(5-chlorobenzo[b]thiophen-3-yl)-2-oxoethyl(methyl)phosphinate-2-carboxylicacid (80 g, 0.24 mole) and DMF (400 mL). To the resulting lightsuspension was added NaHCO₃ (40 g, 0.476 mole), the suspension cooled to4° C. and 1,1′-carbonyldiimidazole (60 g, 0.37 mole) were added. Theresulting mixture was aged for 1 hour while stirring, over which timeoff-gassing was observed to stop and the temperature observed to rise to15° C. The resulting mixture was then cooled to 0° C. and ammonia addeduntil no exotherm was observed. The resulting mixture was cooled to 0°C. and 5% NaHCO₃ (1200 mL) was added over 30 min. The resulting slurrywas stirred and aged at room temperature overnight, then filtered,washed 2 times with 5% NaHCO₃ (500 mL) and 2 times with water (250 m).The filtercake was air dried, then slurried with ethyl acetate (400 m)overnight at room temperature. The resulting mixture was filtered andthe filtercake washed with ethyl acetate (2×50 mL), then dried overnightat 45° C. to yield the title compound as a solid.

Example 9(5-Chloro-benzo[b]thiophen-3-yl)-(ethoxy-methyl-phosphinoyl)-acetic acid

To a dry 4N 300 ml flask equipped with magnetic stirrer, nitrogen inlet,temperature probe and addition port was added ethyl(5-chlorobenzo[b]thiophen-3-yl)methyl(methyl)phosphinate (12.7, 43.99mmol) and dry THF (15 mL) under nitrogen. The resulting solution wascooled to −20° C. To the mixture was then added a 40% (2.2 M) NaHMDSsolution in THF (25 mL), maintaining the temperature below 10° C.Following the base addition, CO₂ was bubbled cautiously until noexotherm was observed, while maintaining the temperature of the reactionmixture below 15° C. The resulting mixture was then degassed withnitrogen and NaHMDS (10 mL) was added, followed by additional CO₂bubbling. The addition of NaHMDS ad CO₂ was repeated 3 more times. Theresulting solution was cooled to 0° C. and MTBE (80 mL) was added. Tothe resulting mixture was then added, slowly, 2N HCl (20 mL), followedby 6N HCl (40 mL), at which point the pH of the mixture was measured tobe about 2. Throughout the addition of the acid, the temperature of themixture was maintained between 0 and 15° C. Initial precipitation wasobserved upon acidification, while on completion of the acid addition,the mixture resolved in two clear layers. The layers were split, and theorganic layer evaporated to yield an oil. The oil was digested overnightwith MTBE (20 mL) to yield the title compound as a filterable solid.

Example 10[Carbamoyl-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-methyl-phosphinicacid ethyl ester

(5-Chloro-benzo[b]thiophen-3-yl)-(ethoxy-methyl-phosphinoyl)-acetic acid(9.0 g, 0.027 mol) was suspended in THF (250 mL), TEA (4.46 mL, 0.032mol), and isobutylchloroformate (3.5 mL, 0.0027 mol) were slowly addedand the resulting suspension cooled to −5° C. The resulting mixture wasstirred for 1 hour at −2° C. and then ammonium acetate (2.1 g, 0.027mol) was added in two portions. The cooling ice bath was then roomed andthe resulting mixture was left overnight. To the resulting mixture wasthen added THF (100 mL) and additional isobutylchloroformate (0.5 ml)and the resulting mixture stirred for 30 minutes. To the resultingmixture was then added ammonium acetate (3.8 mmol) and the resultingmixture again stirred for 30 minutes.

To the resulting mixture was then added water (200 mL). Most of the THFwas then evaporated and ethyl acetate (250 mL) added. To the resultingmixture was then added water (100 mL; for a total water amount of 300mL) and ethyl acetate (150 mL; for a total ethyl acetate amount of 400mL). The resulting mixture was heated to 40° C., the resulting layerswere separated. The organic layer was washed with NaOH (0.1%, 200 mL)and brine (200 mL). The solvent was removed by evaporation to dryness toyield the title compound as a residue, as a white solid.

To the white solid was added acetonitrile (300 mL) and the resultingmixture heated on a steam bath to dissolve the solid. The heated mixturewas then polish filtered through filter paper. The crystallized titlecompound was then isolated as a white solid.

The procedure described in Example 11 below represents a recipe for thepreparation of the title compound. The recipe/procedure was applied tothe preparation of 4 individual batches of the title compound.

Example 11{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinicacid ethyl ester

[Carbamoyl-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-methyl-phosphinicacid ethyl ester (60.0 g, 181 mmol) was placed in a reactor undernitrogen, followed by addition of cesium carbonate (35.3 g, 108 mmol)and copper iodide (6.90 g, 36.2 mmol) and the resulting mixture wasstirred at ambient temperature. DMA (123 g) andN,N′-dimethylethylenediame (6.36 g, 72.1 mmol) (with the addition flaskwashed with DMA (30 g)) were added and the resulting mixture heated to70-75° C. with about 30-60 minutes, over which time a thin bluesuspension was observed to form. To the resulting mixture was then added4-(2-bromo-vinyl)-1,2-difluoro-benzene (47.6 g, 217 mmol) over about10-30 minutes (with the addition flask washed with DMA (30 g)), thenstirred for 5 to 7 hours at 75-85° C., with the progress of the reactionmonitored by HPLC. When the reaction was deemed complete, the reactionmixture was cooled to 60-78° C., ethyl acetate (345 g) was addedfollowed by addition of water (303 g), and the mixture stirred for 10-30minutes. The resulting phases were separated. To the organic phase wasadded a solution of NaCl (30 g in 270 g H₂O), followed by stirring for10-30 min at a temperature of 55-65° C. The resulting phases wereseparated, to the organic phase was added again a solution of NaCl (30 gin 270 g H₂O), followed by stirring for 10-30 min at a temperature of55-65° C. The resulting phases were separated and treated a third timewith addition of a solution of NaCl (30 g in 270 g H₂O), followed bystirring for 10-30 min at a temperature of 55-65° C. The resultingphases were separated, the organic phase heated to distill off 107-139 gof solvent (at 50-65° C.). To the resulting residue, cyclohexane (280 g)was added over 20-40 minutes and the resulting mixture cooled to 10-15°C., then stirred at this temperature for 2-3 hours, over which time athick suspension was observed to form. The resulting suspension wasfiltered, the filtercake washed with a mixture of cyclohexane (135 g)and ethyl acetate (45 g), then dried at 55-60° C., under vacuum to yieldthe title compound as a solid.

Example 12 Oral Formulation—Prophetic Example

As a specific embodiment of an oral composition, 100 mg of the compoundprepared as in Example 1, 2, 3 or 4 is formulated with sufficient finelydivided lactose to provide a total amount of 580 to 590 mg to fill asize 0 hard gel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A process for the preparation of a compound of formula (I)

wherein

is independently selected from the group consisting of aryl, heteroaryl,and benzo fused heterocyclyl; optionally substituted with R² and R³; R²is one to three substituents independently selected from the groupconsisting of C₁₋₄alkyl, methoxy, C₂₋₆alkoxy, NH₂, NH(C₁₋₆alkyl),—N(C₁₋₆)dialkyl, aryl, heteroaryl, halogen, hydroxy, and nitro; whereinthe C₁₋₄alkyl and C₂₋₆ alkoxy substituents of R² are optionallysubstituted with a substituent independently selected from the groupconsisting of —NR¹¹R¹², aryl heteroaryl, one to three halogens andhydroxy; wherein R¹¹ and R¹² are substituents independently selectedfrom the group consisting of hydrogen, C₁₋₆ alkyl, and aryl; wherein theC₁₋₆alkyl substituent of R¹¹ or R¹² is optionally substituted with asubstituent selected from the group consisting of hydroxy, aryl,—C(═O)C₁₋₄alkoxy, and —NR¹⁵R¹⁶; wherein said R¹⁵ and R¹⁶ aresubstituents independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, and aryl, alternatively, R¹⁵ and R¹⁶ are takentogether with the atoms to which they are attached to form a ring offive to seven members; R³ is one to three substituents independentlyselected from the group consisting of C₁₋₆alkyl, C₂₋₆alkenyl,C₁₋₆alkoxy, —OCH₂(C₂₋₆)alkenyl, NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆)dialkyl,—NHC(═O)Cy, —N(C₁₋₆alkyl)C(═O)Cy, —C(═O)C₁₋₄alkoxy, —C(═O)NR¹⁷R¹⁸,—C(═O)NHcycloalkyl, —C(═O)N(C₁₋₆alkyl)cycloalkyl, —C(═O)NHCy,—C(═O)N(C₁₋₆alkyl)Cy, —C(═O)Cy, —OC(═O)NR¹⁹R²⁰, halogen, hydroxy, nitro,cyano, aryl, and aryloxy; wherein alkyl and alkoxy are optionallysubstituted with one to three substituents independently selected fromthe group consisting of —NR²¹R²², —NHcycloalkyl,—N(C₁₋₆alkyl)cycloalkyl, —NHCy, —N(C₁₋₆alkyl)Cy, aryl, heteroaryl,halogen, —C(═O)NR²³R²⁴, —OC(═O)NR²⁵R²⁶, —C(═O)(C₁₋₄)alkoxy, and—C(═O)Cy; wherein alkenyl is optionally substituted on a terminal carbonwith aryl and —C(═O)NR²⁷R²⁸; and, wherein aryl and cycloalkyl areoptionally substituted with one to three substituents independentlyselected from R¹⁴; each R¹⁴ is independently hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy, C₂₋₆alkenyl, C₁₋₆alkylthio, —NH₂, —NH(C₁₋₆)alkyl,—N(C₁₋₆)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen,hydroxy, or nitro; wherein any one of the foregoing C₁₋₆alkyl- orC₁₋₆alkoxy-containing substituents of R¹⁴ is optionally substituted on aterminal carbon atom with a substituent selected from —NR²⁹R³⁰, aryl,heteroaryl, one to three halogen atoms, or hydroxy; R¹⁷, R¹⁸, R¹⁹, R²⁰,R²¹, R²², R²³, R²⁴, R²⁵ and R²⁶ are substituents independently selectedfrom the group consisting of hydrogen, C₁₋₆alkyl and aryl; wherein theC₁₋₆alkyl and aryl are each optionally substituted with hydroxy, aryl,aryloxy, —C(═O)-aryl, —C(═O)C₁₋₄alkoxy, NH₂, —NH(C₁₋₆alkyl), or—N(C₁₋₆)dialkyl; alternatively, R¹⁷ and R¹⁸, R¹⁹ and R²⁰, R²¹ and R²²,R²³ and R²⁴ or R²⁵ and R²⁶ are taken together with the atoms to whichthey are attached to form a ring of five to seven members; R²⁷ and R²⁸are independently hydrogen; C₁₋₆alkyl optionally substituted withhydroxy, aryl, —C(═O)C₁₋₄alkoxy, NH₂, —NH(C₁₋₆alkyl) or —N(C₁₋₆)dialkyl;or aryl; alternatively, R²⁷ and R²⁸ are taken together with the atoms towhich they are attached to form a ring of five to seven members; R²⁹ andR³⁰ are independently hydrogen, C₁₋₆alkyl optionally substituted withhydroxy, aryl, —C(═O)C₁₋₄alkoxy, NH₂, —NH(C₁₋₆alkyl), or—N(C₁₋₆)dialkyl; or aryl; alternatively, R²⁹ and R³⁰ are taken togetherwith the atoms to which they are attached to form a ring of five toseven members; Cy is a heterocyclyl optionally substituted with asubstituent selected from the group consisting of C₁₋₆ alkyl,C₁₋₆alkylC(═O)C₁₋₆alkyl, —C₁₋₆alkylC(═O)C₁₋₆alkoxy, C₁₋₆alkylC(═O)aryl,—C(═O)(C₁₋₆)alkyl, —C(═O)(C₁₋₆)alkoxy, —C(═O)aryl, —SO₂aryl, aryl,heteroaryl, and heterocyclyl; wherein aryl and the aryl portion of theC₁₋₆alkylC(═O)aryl, —C(═O)aryl and —SO₂aryl are optionally substitutedwith one to three substituents independently selected from the groupconsisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen, hydroxy, NH₂,NH(C₁₋₆alkyl), or —N(C₁₋₆)dialkyl; and wherein heterocyclyl isoptionally substituted with aryl, one to three halogen atoms, or one tothree oxo substituents; and, wherein heterocyclyl is optionallyspiro-fused to said Cy; R⁵ is selected from the group consisting ofhydrogen; C₁₋₃alkyl optionally substituted with NH₂, —NH(C₁₋₆)alkyl,—N(C₁₋₆)dialkyl, C₁₋₆alkylcarbonyloxy, C₁₋₆alkoxycarbonyloxy,C₁₋₆alkylcarbonylthio, (C₁₋₆)alkylaminocarbonyl,di(C₁₋₆)alkylaminocarbonyl, one to three halogens, or hydroxy; and aryloptionally substituted with C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylthio, C₂₋₆alkenyl, —NH₂, —NH(C₁₋₆)alkyl, —N(C₁₋₆)dialkyl, aryl, heteroaryl,aryloxy, heteroaryloxy, halogen, hydroxy, or nitro; alternatively, whenR⁶ is C₁₋₈alkoxy, R⁵ and R⁶ are taken together with the atoms to whichthey are attached to form a 5-8 membered monocyclic ring; and providedthat R⁵ is other than C₁₋₃alkyl substituted withdi(C₁₋₆)alkylamino-carbonyl when ring system A is 3,4-difluoro-phenyl,R⁶ is OH, and Z-R⁴ is 5-chloro-benzothiophen-3-yl; and provided that R⁵is other than C₁₋₃alkyl substituted with C₁₋₆alkylcarbonylthio when ringsystem A is 3,4-difluoro-phenyl, R⁶ is CH₃, and Z-R⁴ is5-chloro-benzothiophen-3-yl; R⁶ is selected from the group consisting ofC₁₋₆alkyl, C₁₋₈alkoxy, heteroaryl, aryl, and hydroxy; wherein alkyl andC₁₋₈alkoxy are optionally substituted on a terminal carbon atom with asubstituent selected from C₁₋₃alkoxy, aryl, or hydroxy; and alkoxy isoptionally substituted on a terminal carbon with a substituentindependently selected from the group consisting ofC₁₋₆alkylcarbonyloxy, and di(C₁₋₆)alkylaminocarbonyl; and whereinheteroaryl and aryl are optionally substituted with one to threesubstituents independently selected from the group consisting of aryl,hydroxy, C₁₋₆alkoxy, and halogen. Z is a bicyclic aryl or bicyclicheteroaryl; R⁴ is one to three substituents selected from the groupconsisting of H, C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkoxy, aryl(C₂₋₆)alkenyl,halogen, —C(═O)Cy, —C(═O)NR³¹R³², aryl, —CO₂H, oxo, and cyano; whereinthe alkyl and alkoxy are optionally substituted with a substituentindependently selected from the group consisting of —NR³³R³⁴, aryl, oneto three halogen atoms, and hydroxy; wherein the aryl is optionallysubstituted with a substituent independently selected from the groupconsisting of hydrogen, C₁₋₆alkyl, C₁₋₆alkoxy, aryl, halogen, hydroxy,and nitro; wherein said R³¹, R³², R³³, and R³⁴ are substituentsindependently selected from the group consisting of hydrogen, C₁₋₆alkyl, and aryl, wherein alkyl is optionally substituted with hydroxy,aryl, —C(═O)C₁₋₄alkoxy, NH₂, NH(C₁₋₆alkyl), or —N(C₁₋₆)dialkyl; or R³¹with R³², or R³³ with R³⁴ are optionally taken together with the atomsto which they are attached to form a ring of five to seven members; or apharmaceutically acceptable salt thereof; comprising the steps of

(a) reacting a compound of formula (IV), wherein PG¹ is an oxygenprotecting group; with a source of nitrogen; in the presence of CO₂ gas;in an organic solvent; to yield the corresponding compound of formula(IX);

(b) reacting the compound of formula (IX) with a compound of formula(XVI); in the presence of CuI; in the presence of an inorganic base; inthe presence of a ligand; in an organic solvent or mixture thereof; toyield the corresponding compound of formula (XVII);

(c) de-protecting the compound of formula (XVII); to yield thecorresponding compound of formula (Ia); and

(d) optionally reacting the compound of formula (Ia) with a compound offormula (XVIII), wherein Q¹ is a leaving group and wherein R⁵ is otherthan hydrogen; in the presence of an organic base; in an organicsolvent; to yield the corresponding compound of formula (Ib), wherein R⁵is other than hydrogen.
 2. A process as in claim 1, wherein

is selected from the group consisting of 3,4-difluorophenyl and3,5-dichlorophenyl; R⁵ is selected from the group consisting ofhydrogen; —CH₂—O—C(O)—C(CH₃)₃, and CH₂—OC(O)O—CH(CH₃)₂; R⁶ is selectedfrom the group consisting of methyl and hydroxy; and R⁴-Z is5-chloro-benzo[b]thiophen-3-yl.
 3. A process for the preparation of acompound of formula (I-A)

or a pharmaceutically acceptable salt thereof; comprising the steps of

(a) reacting a compound of formula (IV-S) wherein PG¹ is an oxygenprotecting group with a source of nitrogen, in the presence of CO₂ gas,in an organic solvent; to yield the corresponding compound of formula(IX-S);

(b) reacting the compound of formula (IX-S) with a compound of formula(XVI-A); in the presence of CuI; in the presence of an inorganic base;in the presence of a ligand; in an organic solvent; to yield thecorresponding compound of formula (XVII-A); and

(c) de-protecting the compound of formula (XVII-A); to yield thecorresponding compound of formula (I-A).
 4. A process as in claim 3,wherein the PG¹ is ethyl.
 5. A process as in claim 3, wherein the sourceof nitrogen is LiHMDS and wherein the source of nitrogen is present inan amount in the range of from about 3.0 to about 6.0 molar equivalents.6. A process as in claim 3, wherein the CO₂ is bubbled in an excessamount.
 7. A process as in claim 3, wherein the compound of formula(IV-S) is reacted with the source of nitrogen at a temperature in therange of from about 0° C. to about 20° C.
 8. A process as in claim 3,wherein the compound of formula (XVI-A) is present in an excess of itscorresponding trans orientation; and wherein the compound of formula(XVI-A) is present in an amount in the range of from about 1.0 to about2.0 molar equivalents.
 9. A process as in claim 3, wherein the CuI ispresent in an amount in the range of from about 0.1 to about 0.5 molarequivalents.
 10. A process as in claim 3, wherein the inorganic base instep (b) is Cs₂CO₃ and wherein the Cs₂CO₃ is present in an amount in therange of from about 0.5 to about 3.0 molar equivalents.
 11. A process asin claim 3, wherein the ligand in step (b) isN,N-dimethylethylenediamine, and wherein the ligand is present in anamount in the range of from about 0.2 to about 2.0 molar equivalents.12. A process as in claim 3, wherein the compound of formula (IX-S) isreacted with the compound of formula (XVI-A) at a temperature in therange of from about 50° C. to about 100° C.
 13. A process as in claim 3,wherein the compound of formula (IX-S) is reacted with the compound offormula (XVI-A) under an inert atmosphere.
 14. A process as in claim 3,wherein in step (b) a mixture of the compound of formula (IX-S), theCuI, the ligand, the inorganic base and the organic solvent is heated toa temperature in the range of from about 50° C. to about 100° C., priorto addition of the compound of formula (XVI-A).
 15. A process as inclaim 3, wherein the organic solvent in step (a) is THF and wherein theorganic solvent in step (b) is DMA.
 16. A process for the preparation ofa compound of formula (III)

comprising the step of

(a) reacting a compound of formula (II) with a brominating agent; in thepresence of a catalyst; in a mixture of water and an organic solvent; toyield the corresponding compound of formula (III).
 17. A process as inclaim 16, wherein the compound of formula (II) is present in an excessof its corresponding trans isomer; wherein the brominating agent is1-bromo-pyrrolidine-2,5-dione; wherein the brominating agent is presentin an amount of about 1.1 molar equivalents; wherein the catalyst ismanganese acetate hydrate; wherein the catalyst is present in an amountof about 0.5 molar equivalents; wherein the organic solvent isacetonitrile; and wherein the compound of formula (II) is reacted withbrominating agent at a temperature in the range of from about 25° C. toabout 70° C.
 18. A compound of formula (L)

wherein PG¹ is an oxygen protecting group; R¹⁰ is selected from thegroup consisting of —O-PG² and R⁶; PG² is an oxygen protecting group R⁶is selected from the group consisting of C₁₋₆alkyl, C₁₋₈alkoxy,heteroaryl, aryl, and hydroxy; wherein alkyl and C₁₋₈alkoxy areoptionally substituted on a terminal carbon atom with a substituentselected from C₁₋₃alkoxy, aryl, or hydroxy; and alkoxy is optionallysubstituted on a terminal carbon with a substituent independentlyselected from the group consisting of C₁₋₆alkylcarbonyloxy, anddi(C₁₋₆)alkylaminocarbonyl; and wherein heteroaryl and aryl areoptionally substituted with one to three substituents independentlyselected from the group consisting of aryl, hydroxy, C₁₋₆alkoxy, andhalogen. Z is a bicyclic aryl or bicyclic heteroaryl; R⁴ is one to threesubstituents selected from the group consisting of H, C₁₋₆alkyl,C₁₋₆alkenyl, C₁₋₆alkoxy, aryl(C₂₋₆)alkenyl, halogen, —C(═O)Cy,—C(═O)NR³¹R³², aryl, —CO₂H, oxo, and cyano; wherein the alkyl and alkoxyare optionally substituted with a substituent independently selectedfrom the group consisting of NR³³R³⁴, aryl, one to three halogen atoms,and hydroxy; wherein the aryl is optionally substituted with asubstituent independently selected from the group consisting ofhydrogen, C₁₋₆alkyl, C₁₋₆alkoxy, aryl, halogen, hydroxy, and nitro;wherein said R³¹, R³², R³³, and R³⁴ are substituents independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, and aryl,wherein alkyl is optionally substituted with hydroxy, aryl,—C(═O)C₁₋₄alkoxy, NH₂, NH(C₁₋₆alkyl), or —N(C₁₋₆)dialkyl; or R³¹ withR³², or R³³ with R³⁴ are optionally taken together with the atoms towhich they are attached to form a ring of five to seven members; or apharmaceutically acceptable salt thereof.
 19. A compound as in claim 18,wherein PG¹ is ethyl; R¹⁰ is R⁶; R⁶ is selected from the groupconsisting of methyl and hydroxy; and R⁴-Z is5-chloro-benzo[b]thiophen-3-yl.
 20. A compound as in claim 18, whereinPG¹ is ethyl; R¹⁰ is —O-PG²; PG² is ethyl; and R⁴-Z is5-chloro-benzo[b]thiophen-3-yl.
 21. A process for the preparation of acompound of formula (IX)

wherein PG¹ is an oxygen protecting group; R⁶ is selected from the groupconsisting of C₁₋₆alkyl, C₁₋₈alkoxy, heteroaryl, aryl, and hydroxy;wherein alkyl and C₁₋₈alkoxy are optionally substituted on a terminalcarbon atom with a substituent selected from C₁₋₃alkoxy, aryl, orhydroxy; and alkoxy is optionally substituted on a terminal carbon witha substituent independently selected from the group consisting ofC₁₋₆alkylcarbonyloxy, and di(C₁₋₆)alkylaminocarbonyl; and whereinheteroaryl and aryl are optionally substituted with one to threesubstituents independently selected from the group consisting of aryl,hydroxy, C₁₋₆alkoxy, and halogen. Z is a bicyclic aryl or bicyclicheteroaryl; R⁴ is one to three substituents selected from the groupconsisting of H, C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkoxy, aryl(C₂₋₆)alkenyl,halogen, —C(═O)Cy, —C(═O)NR³¹R³², aryl, —CO₂H, oxo, and cyano; whereinthe alkyl and alkoxy are optionally substituted with a substituentindependently selected from the group consisting of —NR³³R³⁴, aryl, oneto three halogen atoms, and hydroxy; wherein the aryl is optionallysubstituted with a substituent independently selected from the groupconsisting of hydrogen, C₁₋₆alkyl, C₁₋₆alkoxy, aryl, halogen, hydroxy,and nitro; wherein said R³¹, R³², R³³, and R³⁴ are substituentsindependently selected from the group consisting of hydrogen, C₁₋₆alkyl, and aryl, wherein alkyl is optionally substituted with hydroxy,aryl, —C(═O)C₁₋₄alkoxy, NH₂, NH(C₁₋₆alkyl), or —N(C₁₋₆)dialkyl; or R³¹with R³², or R³³ with R³⁴ are optionally taken together with the atomsto which they are attached to form a ring of five to seven members; or apharmaceutically acceptable salt thereof; comprising the step of

(a) reacting a compound of formula (IV) with a source of nitrogen; inthe presence of CO₂ gas; in an organic solvent; to yield thecorresponding compound of formula (IX).
 22. A process as in claim 21,wherein PG¹ is ethyl, R⁶ is selected from the group consisting of methyland hydroxy, and R⁴-Z is 5-chloro-benzo[b]thiophen-3-yl.
 23. A processfor the preparation of a compound of formula (IX-S)

comprising

(a) reacting a compound of formula (IV-S) wherein PG¹ is an oxygenprotecting group with a source of nitrogen, in the presence of CO₂ gas,in an organic solvent; to yield the corresponding compound of formula(IX-S).
 24. A process as in claim 23 wherein PG¹ is ethyl; wherein thesource of nitrogen is LiHMDS; wherein the source of nitrogen is presentin an amount in the range of from about 3.0 to about 6.0 molarequivalents; and wherein the CO₂ gas is bubbled in an excess amount.